Photoredox-Catalyzed Direct C-H Functionalization of Arenes

ABSTRACT

The invention generally relates to methods of making substituted arenes via direct C—H amination. More specifically, methods of making para- and ortho-substituted arenes via direct C—H amination are disclosed. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.15/826,092, filed Nov. 29, 2017, which is a continuation ofInternational Application No. PCT/US2016/035549 with an internationalfiling date of Jun. 2, 2016, which claims priority to U.S. ProvisionalApplication No. 62/170,632 filed on Jun. 3, 2015, the contents of whichare incorporated herein by reference in their entireties.

BACKGROUND

Nitrogen-containing aromatic compounds are extremely important in thesynthesis of pharmaceuticals and commodity chemicals. As such, newmethods for the construction of nitrogen substituted arenes are in highdemand. To achieve aryl C—N bond formation, previous methodologies havegenerally required a pre-installed functional handle on the arene inorder to introduce the amine via a cross-coupling strategy (Belfield etal. (1999) Tetrahedron 55, 11399; Surry and Buchwald (2011) Chem. Soc.2, 27; Hartwig (2008) Acc. Chem. Res. 41, 1534). More recent work hasdemonstrated the utility of arene C—H functionalization as acomparatively expedient strategy for the construction of N-arylatedproducts; however, these methodologies are limited by several factors.The regiochemical outcome is largely dictated by a pre-installed Lewisbasic directing group, which typically results in ortho selectivity(Tsang et al. (2005) J. Am. Chem. Soc. 127, 14560; Antonchick et al.(2011) Angew. Chem. Int. Ed. 50, 8605; Matsubara et al. (2014) J. Am.Chem. Soc. 136, 646; Tran et al. (2013) Angew. Chem. Int. Ed. 52, 6043).In the rare examples of arene amination where ortho addition issuppressed, differentiation between meta and para positions is notobserved (Shrestha et al. (2013) J. Am. Chem. Soc. 135, 8480).Additionally, these protocols often require superstoichiometricequivalents of both arene and a terminal oxidant in order to achievesynthetically useful yields (Allen et al. (2014) J. Am. Chem. Soc. 136,5607; Brachet et al. (2015) Chem. Sci. Advance Article; Marchetti et al.Org. Lett. ASAP), limiting the value of this method as a tool for latestage functionalization. Despite recent advances in arene C—Hfunctionalization, this methodology has continued to be restricted bythe regioselectivity of the reaction and the substrate scope. Thus,there remains a need for direct aryl amination reactions that aretolerant to a wide range of substrates and that are regioselective.

SUMMARY

In accordance with the purpose(s) of the invention, as embodied andbroadly described herein, the invention, in one aspect, relates tomethods of synthesizing a substituted arene via direct C—Hfunctionalization (e.g., amination).

Disclosed are methods of making a compound having a structurerepresented by a formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl; wherein Z is selected from halogen, —CN, —NH₂, —OH, C1-C8alkenyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, arylamino, diarylamino, C1-C8 alkarylamino,—NNR⁴, —OC(═O)R⁵, and Ar¹; wherein R⁴ is selected from hydrogen andC1-C8 alkyl; wherein R⁵ is selected from C1-C8 alkyl; wherein Ar¹ is a3- to 6-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from halogen and C1-C8 alkyl, the methodcomprising the steps of: (a) reacting a compound having a structurerepresented by a formula:

with a nucleophile selected from water, ammonia, a halide, a cyanide, analcohol, a thiol, an amine, a hydrazine, a carbamate, a carboxylic acid,and an alkene, in the presence of a catalytically effective amount of anacridinium photocatalyst; and (b) reacting with an oxidant, therebyforming the compound.

Also disclosed are methods of making a compound having a structurerepresented by a formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl; or wherein each of Q² and Q⁴ is CR² and wherein eachoccurrence of R² are optionally covalently bonded and, together with theintermediate atoms, comprise a 5- to 6-membered cycle or heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); wherein Zis selected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8 alkoxy,C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; wherein Ar¹ is a 3- to 6-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen and C1-C8 alkyl, the method comprising the steps of: (a)reacting a compound having a structure represented by a formula:

with a nucleophile selected from water, ammonia, a halide, a cyanide, analcohol, a thiol, an amine, a hydrazine, a carbamate, a carboxylic acid,and an alkene, in the presence of a catalytically effective amount of anacridinium photocatalyst; and (b) reacting with an oxidant, therebyforming the compound.

Also disclosed are methods of making a compound having a structurerepresented by a formula selected from:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle substituted with 0, 1, 2, or 3groups independently selected from halogen, C1-C8 alkyl, C1-C8 alkoxy,and —C(═O)NR^(3a)R^(3b); wherein each of R^(3a) and R^(3b) isindependently selected from hydrogen and C1-C4 alkyl; wherein Z isselected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8 alkoxy,C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; and wherein Ar¹ is a 3- to 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen and C1-C8 alkyl, the method comprising the steps of: (a)reacting a compound having a structure represented by a formula selectedfrom:

with a nucleophile selected from water, ammonia, a halide, a cyanide, analcohol, a thiol, an amine, a hydrazine, a carbamate, a carboxylic acid,and an alkene, in the presence of a catalytically effective amount of anacridinium photocatalyst; and (b) reacting with an oxidant, therebyforming the compound are disclosed. In a further aspect, the electrondonating group is selected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8alkoxy, C1-C8 thioalkoxy, C1-C8 silyloxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, —OAr², and Ar²;wherein each of R⁶ and R⁷ is independently selected from C1-C8 alkyl;and wherein Ar² is selected from aryl and heteroaryl and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen and C1-C8alkyl.

Also disclosed are methods of C—H functionalization (e.g., amination) anactivated arene in the presence of an acridinium photocatalyst.

Also disclosed are methods of C—H functionalization (e.g., amination) anactivated arene in the absence of a transition metal catalyst.

Also disclosed are compounds having a structure represented by aformula:

wherein X is selected from BF₄, TfO, PF₆, and ClO₄; wherein each ofR^(8a), R^(8b), R^(8c), R^(8d), R^(8a′), R^(8b′), R^(8c′), and R^(8d′)is independently selected from hydrogen, halogen, —CF₃, —NH₂, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 dialkylamino, and phenylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4dialkylamino; wherein R⁹ is selected from C1-C4 alkyl and phenylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino; and wherein R¹⁰ is selected from C1-C4alkyl and phenyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen and C1-C4 alkyl.

Also disclosed are catalyst systems comprising an acridiniumphotocatalyst, a nucleophile, and an oxidant.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying FIGURES, which are incorporated in and constitute apart of this specification, illustrate several aspects and together withthe description serve to explain the principles of the invention.

FIG. 1 shows representative data indicating that the reaction yield isroughly correlated with the pKa of the conjugate acid.

Additional advantages of the invention will be set forth in part in thedescription which follows, and in part will be obvious from thedescription, or can be learned by practice of the invention. Theadvantages of the invention will be realized and attained by means ofthe elements and combinations particularly pointed out in the appendedclaims. It is to be understood that both the foregoing generaldescription and the following detailed description are exemplary andexplanatory only and are not restrictive of the invention, as claimed.

DETAILED DESCRIPTION

The present invention can be understood more readily by reference to thefollowing detailed description of the invention and the Examplesincluded therein.

Before the present compounds, compositions, articles, systems, devices,and/or methods are disclosed and described, it is to be understood thatthey are not limited to specific synthetic methods unless otherwisespecified, or to particular reagents unless otherwise specified, as suchmay, of course, vary. It is also to be understood that the terminologyused herein is for the purpose of describing particular aspects only andis not intended to be limiting. Although any methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, example methods andmaterials are now described.

While aspects of the present invention can be described and claimed in aparticular statutory class, such as the system statutory class, this isfor convenience only and one of skill in the art will understand thateach aspect of the present invention can be described and claimed in anystatutory class. Unless otherwise expressly stated, it is in no wayintended that any method or aspect set forth herein be construed asrequiring that its steps be performed in a specific order. Accordingly,where a method claim does not specifically state in the claims ordescriptions that the steps are to be limited to a specific order, it isno way intended that an order be inferred, in any respect. This holdsfor any possible non-express basis for interpretation, including mattersof logic with respect to arrangement of steps or operational flow, plainmeaning derived from grammatical organization or punctuation, or thenumber or type of aspects described in the specification.

Throughout this application, various publications are referenced. Thedisclosures of these publications in their entireties are herebyincorporated by reference into this application in order to more fullydescribe the state of the art to which this pertains. The referencesdisclosed are also individually and specifically incorporated byreference herein for the material contained in them that is discussed inthe sentence in which the reference is relied upon. Nothing herein is tobe construed as an admission that the present invention is not entitledto antedate such publication by virtue of prior invention. Further, thedates of publication provided herein may be different from the actualpublication dates, which can require independent confirmation.

A. Definitions

As used herein, nomenclature for compounds, including organic compounds,can be given using common names, IUPAC, IUBMB, or CAS recommendationsfor nomenclature. When one or more stereochemical features are present,Cahn-Ingold-Prelog rules for stereochemistry can be employed todesignate stereochemical priority, E/Z specification, and the like. Oneof skill in the art can readily ascertain the structure of a compound ifgiven a name, either by systemic reduction of the compound structureusing naming conventions, or by commercially available software, such asCHEMDRAW™ (Cambridgesoft Corporation, U.S.A.).

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a functionalgroup,” “an alkyl,” or “a residue” includes mixtures of two or more suchfunctional groups, alkyls, or residues, and the like.

Ranges can be expressed herein as from “about” one particular value,and/or to “about” another particular value. When such a range isexpressed, a further aspect includes from the one particular valueand/or to the other particular value. Similarly, when values areexpressed as approximations, by use of the antecedent “about,” it willbe understood that the particular value forms a further aspect. It willbe further understood that the endpoints of each of the ranges aresignificant both in relation to the other endpoint, and independently ofthe other endpoint. It is also understood that there are a number ofvalues disclosed herein, and that each value is also herein disclosed as“about” that particular value in addition to the value itself. Forexample, if the value “10” is disclosed, then “about 10” is alsodisclosed. It is also understood that each unit between two particularunits are also disclosed. For example, if 10 and 15 are disclosed, then11, 12, 13, and 14 are also disclosed.

References in the specification and concluding claims to parts by weightof a particular element or component in a composition denotes the weightrelationship between the element or component and any other elements orcomponents in the composition or article for which a part by weight isexpressed. Thus, in a compound containing 2 parts by weight of componentX and 5 parts by weight component Y, X and Y are present at a weightratio of 2:5, and are present in such ratio regardless of whetheradditional components are contained in the compound.

A weight percent (wt. %) of a component, unless specifically stated tothe contrary, is based on the total weight of the formulation orcomposition in which the component is included.

As used herein, the terms “optional” or “optionally” means that thesubsequently described event or circumstance can or cannot occur, andthat the description includes instances where said event or circumstanceoccurs and instances where it does not.

As used herein, the term “catalytically effective” refers to the amountof a catalyst that is sufficient to facilitate a reaction (e.g., C—Hfunctionalization (e.g., amination) as disclosed herein).

As used herein, the term “derivative” refers to a compound having astructure derived from the structure of a parent compound (e.g., acompound disclosed herein) and whose structure is sufficiently similarto those disclosed herein and based upon that similarity, would beexpected by one skilled in the art to exhibit the same or similaractivities and utilities as the claimed compounds, or to induce, as aprecursor, the same or similar activities and utilities as the claimedcompounds. Exemplary derivatives include salts, esters, amides, salts ofesters or amides, and N-oxides of a parent compound.

A residue of a chemical species, as used in the specification andconcluding claims, refers to the moiety that is the resulting product ofthe chemical species in a particular reaction scheme or subsequentformulation or chemical product, regardless of whether the moiety isactually obtained from the chemical species. Thus, an ethylene glycolresidue in a polyester refers to one or more —OCH₂CH₂O— units in thepolyester, regardless of whether ethylene glycol was used to prepare thepolyester. Similarly, a sebacic acid residue in a polyester refers toone or more —CO(CH₂)₈CO— moieties in the polyester, regardless ofwhether the residue is obtained by reacting sebacic acid or an esterthereof to obtain the polyester.

As used herein, the term “substituted” is contemplated to include allpermissible substituents of organic compounds. In a broad aspect, thepermissible substituents include acyclic and cyclic, branched andunbranched, carbocyclic and heterocyclic, and aromatic and nonaromaticsubstituents of organic compounds. Illustrative substituents include,for example, those described below. The permissible substituents can beone or more and the same or different for appropriate organic compounds.For purposes of this disclosure, the heteroatoms, such as nitrogen, canhave hydrogen substituents and/or any permissible substituents oforganic compounds described herein which satisfy the valences of theheteroatoms. This disclosure is not intended to be limited in any mannerby the permissible substituents of organic compounds. Also, the terms“substitution” or “substituted with” include the implicit proviso thatsuch substitution is in accordance with permitted valence of thesubstituted atom and the substituent, and that the substitution resultsin a stable compound, e.g., a compound that does not spontaneouslyundergo transformation such as by rearrangement, cyclization,elimination, etc. It is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

In defining various terms, “A¹,” “A²,” “A³,” and “A⁴” are used herein asgeneric symbols to represent various specific substituents. Thesesymbols can be any substituent, not limited to those disclosed herein,and when they are defined to be certain substituents in one instance,they can, in another instance, be defined as some other substituents.

The term “aliphatic” or “aliphatic group,” as used herein, denotes ahydrocarbon moiety that may be straight-chain (i.e., unbranched),branched, or cyclic (including fused, bridging, and spirofusedpolycyclic) and may be completely saturated or may contain one or moreunits of unsaturation, but which is not aromatic. Unless otherwisespecified, aliphatic groups contain 1-20 carbon atoms. Aliphatic groupsinclude, but are not limited to, linear or branched, alkyl, alkenyl, andalkynyl groups, and hybrids thereof such as (cycloalkyl)alkyl,(cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “alkyl” as used herein is a branched or unbranched saturatedhydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl,isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. Thealkyl group can be cyclic or acyclic. The alkyl group can be branched orunbranched. The alkyl group can also be substituted or unsubstituted.For example, the alkyl group can be substituted with one or more groupsincluding, but not limited to, alkyl, cycloalkyl, alkoxy, amino, ether,halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol, as described herein.A “lower alkyl” group is an alkyl group containing from one to six(e.g., from one to four) carbon atoms.

Throughout the specification “alkyl” is generally used to refer to bothunsubstituted alkyl groups and substituted alkyl groups; however,substituted alkyl groups are also specifically referred to herein byidentifying the specific substituent(s) on the alkyl group. For example,the term “halogenated alkyl” or “haloalkyl” specifically refers to analkyl group that is substituted with one or more halide, e.g., fluorine,chlorine, bromine, or iodine. The term “alkoxyalkyl” specifically refersto an alkyl group that is substituted with one or more alkoxy groups, asdescribed below. The term “alkylamino” specifically refers to an alkylgroup that is substituted with one or more amino groups, as describedbelow, and the like. When “alkyl” is used in one instance and a specificterm such as “alkylalcohol” is used in another, it is not meant to implythat the term “alkyl” does not also refer to specific terms such as“alkylalcohol” and the like.

This practice is also used for other groups described herein. That is,while a term such as “cycloalkyl” refers to both unsubstituted andsubstituted cycloalkyl moieties, the substituted moieties can, inaddition, be specifically identified herein; for example, a particularsubstituted cycloalkyl can be referred to as, e.g., an“alkylcycloalkyl.” Similarly, a substituted alkoxy can be specificallyreferred to as, e.g., a “halogenated alkoxy,” a particular substitutedalkenyl can be, e.g., an “alkenylalcohol,” and the like. Again, thepractice of using a general term, such as “cycloalkyl,” and a specificterm, such as “alkylcycloalkyl,” is not meant to imply that the generalterm does not also include the specific term.

The term “cycloalkyl” as used herein is a non-aromatic carbon-based ringcomposed of at least three carbon atoms. Examples of cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like. The term “heterocycloalkyl” is atype of cycloalkyl group as defined above, and is included within themeaning of the term “cycloalkyl,” where at least one of the carbon atomsof the ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkyl group andheterocycloalkyl group can be substituted or unsubstituted. Thecycloalkyl group and heterocycloalkyl group can be substituted with oneor more groups including, but not limited to, alkyl, cycloalkyl, alkoxy,amino, ether, halide, hydroxy, nitro, silyl, sulfo-oxo, or thiol asdescribed herein.

The term “polyalkylene group” as used herein is a group having two ormore CH₂ groups linked to one another. The polyalkylene group can berepresented by the formula —(CH₂)_(a)—, where “a” is an integer of from2 to 500.

The terms “alkoxy” and “alkoxyl” as used herein to refer to an alkyl orcycloalkyl group bonded through an ether linkage; that is, an “alkoxy”group can be defined as —OA¹ where A¹ is alkyl or cycloalkyl as definedabove. “Alkoxy” also includes polymers of alkoxy groups as justdescribed; that is, an alkoxy can be a polyether such as —OA¹-OA² or—OA¹-(OA²)_(a)—OA³, where “a” is an integer of from 1 to 200 and A¹, A²,and A³ are alkyl and/or cycloalkyl groups.

The term “alkenyl” as used herein is a hydrocarbon group of from 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon double bond. Asymmetric structures such as (A¹A²)C═C(A³A⁴)are intended to include both the E and Z isomers. This can be presumedin structural formulae herein wherein an asymmetric alkene is present,or it can be explicitly indicated by the bond symbol C═C. The alkenylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, orthiol, as described herein.

The term “cycloalkenyl” as used herein is a non-aromatic carbon-basedring composed of at least three carbon atoms and containing at least onecarbon-carbon double bound, i.e., C═C. Examples of cycloalkenyl groupsinclude, but are not limited to, cyclopropenyl, cyclobutenyl,cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl,norbornenyl, and the like. The term “heterocycloalkenyl” is a type ofcycloalkenyl group as defined above, and is included within the meaningof the term “cycloalkenyl,” where at least one of the carbon atoms ofthe ring is replaced with a heteroatom such as, but not limited to,nitrogen, oxygen, sulfur, or phosphorus. The cycloalkenyl group andheterocycloalkenyl group can be substituted or unsubstituted. Thecycloalkenyl group and heterocycloalkenyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “alkynyl” as used herein is a hydrocarbon group of 2 to 24carbon atoms with a structural formula containing at least onecarbon-carbon triple bond. The alkynyl group can be unsubstituted orsubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester, ether,halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiol, asdescribed herein.

The term “cycloalkynyl” as used herein is a non-aromatic carbon-basedring composed of at least seven carbon atoms and containing at least onecarbon-carbon triple bound. Examples of cycloalkynyl groups include, butare not limited to, cycloheptynyl, cyclooctynyl, cyclononynyl, and thelike. The term “heterocycloalkynyl” is a type of cycloalkenyl group asdefined above, and is included within the meaning of the term“cycloalkynyl,” where at least one of the carbon atoms of the ring isreplaced with a heteroatom such as, but not limited to, nitrogen,oxygen, sulfur, or phosphorus. The cycloalkynyl group andheterocycloalkynyl group can be substituted or unsubstituted. Thecycloalkynyl group and heterocycloalkynyl group can be substituted withone or more groups including, but not limited to, alkyl, cycloalkyl,alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, heteroaryl,aldehyde, amino, carboxylic acid, ester, ether, halide, hydroxy, ketone,azide, nitro, silyl, sulfo-oxo, or thiol as described herein.

The term “aromatic group” as used herein refers to a ring structurehaving cyclic clouds of delocalized π electrons above and below theplane of the molecule, where the π clouds contain (4n+2) π electrons. Afurther discussion of aromaticity is found in Morrison and Boyd, OrganicChemistry, (5th Ed., 1987), Chapter 13, entitled “Aromaticity,” pages477-497, incorporated herein by reference. The term “aromatic group” isinclusive of both aryl and heteroaryl groups.

The term “aryl” as used herein is a group that contains any carbon-basedaromatic group including, but not limited to, benzene, naphthalene,phenyl, biphenyl, phenoxybenzene, and the like. The term “aryl” alsoincludes “heteroaryl,” which is defined as a group that contains anaromatic group that has at least one heteroatom incorporated within thering of the aromatic group. Examples of heteroatoms include, but are notlimited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term“non-heteroaryl,” which is also included in the term “aryl,” defines agroup that contains an aromatic group that does not contain aheteroatom. The aryl group can be substituted or unsubstituted. The arylgroup can be substituted with one or more groups including, but notlimited to, alkyl, cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, heteroaryl, aldehyde, amino, carboxylic acid, ester,ether, halide, hydroxy, ketone, azide, nitro, silyl, sulfo-oxo, or thiolas described herein. The term “biaryl” is a specific type of aryl groupand is included in the definition of “aryl.” Biaryl refers to two arylgroups that are bound together via a fused ring structure, as innaphthalene, or are attached via one or more carbon-carbon bonds, as inbiphenyl.

The term “aldehyde” as used herein is represented by the formula —C(O)H.Throughout this specification “C(O)” is a short hand notation for acarbonyl group, i.e., C═O.

The terms “amine” or “amino” as used herein are represented by theformula —NA¹A², where A¹ and A² can be, independently, hydrogen oralkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “alkylamino” as used herein is represented by the formula—NH(-alkyl) where alkyl is a described herein. Representative examplesinclude, but are not limited to, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, (sec-butyl)amino group, (tert-butyl)amino group, pentylaminogroup, isopentylamino group, (tert-pentyl)amino group, hexylamino group,and the like.

The term “dialkylamino” as used herein is represented by the formula—N(-alkyl)₂ where alkyl is a described herein. Representative examplesinclude, but are not limited to, dimethylamino group, diethylaminogroup, dipropylamino group, diisopropylamino group, dibutylamino group,diisobutylamino group, di(sec-butyl)amino group, di(tert-butyl)aminogroup, dipentylamino group, diisopentylamino group, di(tert-pentyl)aminogroup, dihexylamino group, N-ethyl-N-methylamino group,N-methyl-N-propylamino group, N-ethyl-N-propylamino group and the like.

The term “carboxylic acid” as used herein is represented by the formula—C(O)OH.

The term “ester” as used herein is represented by the formula —OC(O)A¹or —C(O)OA¹, where A¹ can be alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group as described herein.The term “polyester” as used herein is represented by the formula-(A¹O(O)C-A²-C(O)O)_(a)— or -(A¹O(O)C-A²-OC(O))_(a)—, where A¹ and A²can be, independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl,alkynyl, cycloalkynyl, aryl, or heteroaryl group described herein and“a” is an integer from 1 to 500. “Polyester” is as the term used todescribe a group that is produced by the reaction between a compoundhaving at least two carboxylic acid groups with a compound having atleast two hydroxyl groups.

The term “ether” as used herein is represented by the formula A¹OA²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group describedherein. The term “polyether” as used herein is represented by theformula -(A¹O-A²O)_(a)—, where A¹ and A² can be, independently, analkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group described herein and “a” is an integer of from 1 to500. Examples of polyether groups include polyethylene oxide,polypropylene oxide, and polybutylene oxide.

The terms “halo,” “halogen” or “halide”, as used herein can be usedinterchangeably and refer to F, Cl, Br, or I.

The terms “pseudohalide,” “pseudohalogen” or “pseudohalo,” as usedherein can be used interchangeably and refer to functional groups thatbehave substantially similar to halides. Such functional groups include,by way of example, cyano, thiocyanato, azido, trifluoromethyl,trifluoromethoxy, perfluoroalkyl, and perfluoroalkoxy groups.

The term “heteroalkyl,” as used herein refers to an alkyl groupcontaining at least one heteroatom. Suitable heteroatoms include, butare not limited to, O, N, Si, P and S, wherein the nitrogen, phosphorousand sulfur atoms are optionally oxidized, and the nitrogen heteroatom isoptionally quaternized. Heteroalkyls can be substituted as defined abovefor alkyl groups.

The term “heteroaryl,” as used herein refers to an aromatic group thathas at least one heteroatom incorporated within the ring of the aromaticgroup. Examples of heteroatoms include, but are not limited to,nitrogen, oxygen, sulfur, and phosphorus, where N-oxides, sulfur oxides,and dioxides are permissible heteroatom substitutions. The heteroarylgroup can be substituted or unsubstituted. The heteroaryl group can besubstituted with one or more groups including, but not limited to,alkyl, cycloalkyl, alkoxy, amino, ether, halide, hydroxy, nitro, silyl,sulfo-oxo, or thiol as described herein. Heteroaryl groups can bemonocyclic, or alternatively fused ring systems. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrimidinyl,tetrazolyl, thienyl, pyridinyl, pyrrolyl, N-methylpyrrolyl, quinolinyl,isoquinolinyl, pyrazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl,oxadiazolyl, thiadiazolyl, isothiazolyl, pyridazinyl, pyrazinyl,benzofuranyl, benzodioxolyl, benzothiophenyl, indolyl, indazolyl,benzimidazolyl, imidazopyridinyl, pyrazolopyridinyl, andpyrazolopyrimidinyl. Further not limiting examples of heteroaryl groupsinclude, but are not limited to, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiophenyl, pyrazolyl, imidazolyl, benzo[d]oxazolyl,benzo[d]thiazolyl, quinolinyl, quinazolinyl, indazolyl,imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazolyl, andpyrido[2,3-b]pyrazinyl.

The term “heterocycle,” as used herein refers to single and multi-cyclicaromatic or non-aromatic ring systems in which at least one of the ringmembers is other than carbon. Heterocycle includes pyridinde,pyrimidine, furan, thiophene, pyrrole, isoxazole, isothiazole, pyrazole,oxazole, thiazole, imidazole, oxazole, including, 1,2,3-oxadiazole,1,2,5-oxadiazole and 1,3,4-oxadiazole, thiadiazole, including,1,2,3-thiadiazole, 1,2,5-thiadiazole, and 1,3,4-thiadiazole, triazole,including, 1,2,3-triazole, 1,3,4-triazole, tetrazole, including1,2,3,4-tetrazole and 1,2,4,5-tetrazole, pyridine, pyridazine,pyrimidine, pyrazine, triazine, including 1,2,4-triazine and1,3,5-triazine, tetrazine, including 1,2,4,5-tetrazine, pyrrolidine,piperidine, piperazine, morpholine, azetidine, tetrahydropyran,tetrahydrofuran, dioxane, and the like.

The term “bicyclic heterocycle” or “bicyclic heterocyclyl,” as usedherein refers to a ring system in which at least one of the ring membersis other than carbon. Bicyclic heterocyclyl encompasses ring systemswherein an aromatic ring is fused with another aromatic ring, or whereinan aromatic ring is fused with a non-aromatic ring. Bicyclicheterocyclyl encompasses ring systems wherein a benzene ring is fused toa 5- or a 6-membered ring containing 1, 2 or 3 ring heteroatoms orwherein a pyridine ring is fused to a 5- or a 6-membered ring containing1, 2 or 3 ring heteroatoms. Bicyclic heterocyclic groups include, butare not limited to, indolyl, indazolyl, pyrazolo[1,5-a]pyridinyl,benzofuranyl, quinolinyl, quinoxalinyl, 1,3-benzodioxolyl,2,3-dihydro-1,4-benzodioxinyl, 3,4-dihydro-2H-chromenyl,1H-pyrazolo[4,3-c]pyridin-3-yl; 1H-pyrrolo[3,2-b]pyridin-3-yl; and1H-pyrazolo[3,2-b]pyridin-3-yl.

The term “heterocycloalkyl” as used herein refers to an aliphatic,partially unsaturated or fully saturated, 3- to 14-membered ring system,including single rings of 3 to 8 atoms and bi- and tricyclic ringsystems. The heterocycloalkyl ring-systems include one to fourheteroatoms independently selected from oxygen, nitrogen, and sulfur,wherein a nitrogen and sulfur heteroatom optionally can be oxidized anda nitrogen heteroatom optionally can be substituted. Representativeheterocycloalkyl groups include, but are not limited to, pyrrolidinyl,pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl,piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl,isothiazolidinyl, and tetrahydrofuryl.

The term “hydroxyl” or “hydroxyl” as used herein is represented by theformula —OH.

The term “ketone” as used herein is represented by the formula A¹C(O)A²,where A¹ and A² can be, independently, an alkyl, cycloalkyl, alkenyl,cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl group asdescribed herein.

The term “azide” or “azido” as used herein is represented by the formula—N₃.

The term “nitro” as used herein is represented by the formula —NO₂.

The term “nitrile” or “cyano” as used herein is represented by theformula —CN.

The term “silyl” as used herein is represented by the formula —SiA¹A²A³,where A¹, A², and A³ can be, independently, hydrogen or an alkyl,cycloalkyl, alkoxy, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl,or heteroaryl group as described herein.

The term “sulfo-oxo” as used herein is represented by the formulas—S(O)A¹, —S(O)₂A¹, —OS(O)₂A¹, or —OS(O)₂OA¹, where A¹ can be hydrogen oran alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl,aryl, or heteroaryl group as described herein. Throughout thisspecification “S(O)” is a short hand notation for S═O. The term“sulfonyl” is used herein to refer to the sulfo-oxo group represented bythe formula —S(O)₂A¹, where A¹ can be hydrogen or an alkyl, cycloalkyl,alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, or heteroaryl groupas described herein. The term “sulfone” as used herein is represented bythe formula A'S(O)₂A², where A¹ and A² can be, independently, an alkyl,cycloalkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkynyl, aryl, orheteroaryl group as described herein. The term “sulfoxide” as usedherein is represented by the formula A'S(O)A², where A¹ and A² can be,independently, an alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl,cycloalkynyl, aryl, or heteroaryl group as described herein.

The term “thiol” as used herein is represented by the formula —SH.

“R¹,” “R²,” “R³,” “R^(n),” where n is an integer, as used herein can,independently, possess one or more of the groups listed above. Forexample, if R¹ is a straight chain alkyl group, one of the hydrogenatoms of the alkyl group can optionally be substituted with a hydroxylgroup, an alkoxy group, an alkyl group, a halide, and the like.Depending upon the groups that are selected, a first group can beincorporated within second group or, alternatively, the first group canbe pendant (i.e., attached) to the second group. For example, with thephrase “an alkyl group comprising an amino group,” the amino group canbe incorporated within the backbone of the alkyl group. Alternatively,the amino group can be attached to the backbone of the alkyl group. Thenature of the group(s) that is (are) selected will determine if thefirst group is embedded or attached to the second group.

As described herein, compounds of the invention may contain “optionallysubstituted” moieties. In general, the term “substituted,” whetherpreceded by the term “optionally” or not, means that one or morehydrogens of the designated moiety are replaced with a suitablesubstituent. Unless otherwise indicated, an “optionally substituted”group may have a suitable substituent at each substitutable position ofthe group, and when more than one position in any given structure may besubstituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. In is also contemplated that, in certain aspects,unless expressly indicated to the contrary, individual substituents canbe further optionally substituted (i.e., further substituted orunsubstituted).

The term “stable,” as used herein, refers to compounds that are notsubstantially altered when subjected to conditions to allow for theirproduction, detection, and, in certain aspects, their recovery,purification, and use for one or more of the purposes disclosed herein.

Suitable monovalent substituents on a substitutable carbon atom of an“optionally substituted” group is independently halogen; —(CH₂)₀₋₄R^(∘);—(CH₂)₀₋₄OR^(∘); —O(CH₂)₀₋₄R^(∘), —O—(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄CH(OR^(∘))₂; —(CH₂)₀₋₄SR^(∘); —(CH₂)₀₋₄Ph, which may besubstituted with R^(∘); —(CH₂)₀₋₄O(CH₂)₀₋₁Ph which may be substitutedwith R^(∘); —CH═CHPh, which may be substituted with R^(∘);—(CH₂)₀₋₄O(CH₂)₀₋₁-pyridyl which may be substituted with R^(∘); —NO₂;—CN; —N₃; —(CH₂)₀₋₄N(R^(∘))₂; —(CH₂)₀₋₄N(R^(∘))C(O)R^(∘);—N(R^(∘))C(S)R^(∘); —(CH₂)₀₋₄N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))C(S)NR^(∘)₂; —(CH₂)₀₋₄N(R^(∘))C(O)OR^(∘); —N(R^(∘))N(R^(∘))C(O)R^(∘);—N(R^(∘))N(R^(∘))C(O)NR^(∘) ₂; —N(R^(∘))N(R^(∘))C(O)OR^(∘);—(CH₂)₀₋₄C(O)R^(∘); —C(S)R^(∘); —(CH₂)₀₋₄C(O)OR^(∘);—(CH₂)₀₋₄C(O)SR^(∘); —(CH₂)₀₋₄C(O)OSiR^(∘) ₃; —(CH₂)₀₋₄OC(O)R^(∘);—OC(O)(CH₂)₀₋₄SR—, SC(S)SR^(∘); —(CH₂)₀₋₄SC(O)R^(∘); —(CH₂)₀₋₄C(O)NR^(∘)₂; —C(S)NR^(∘) ₂; —C(S)SR^(∘); —SC(S)SR^(∘), —(CH₂)₀₋₄OC(O)NR^(∘) ₂;—C(O)N(OR^(∘))R^(∘); —C(O)C(O)R^(∘); —C(O)CH₂C(O)R^(∘);—C(NOR^(∘))R^(∘); —(CH₂)₀₋₄SSR^(∘); —(CH₂)₀₋₄S(O)₂R^(∘);—(CH₂)₀₋₄S(O)₂OR^(∘); —(CH₂)₀₋₄OS(O)₂R^(∘); —S(O)₂NR^(∘) ₂;—(CH₂)₀₋₄S(O)R^(∘) ₂; —N(R^(∘))S(O)₂NR^(∘) ₂; —N(R^(∘))S(O)₂R^(∘);—N(OR^(∘))R^(∘); —C(NH)NR^(∘) ₂; —P(O)₂R^(∘); —P(O)R^(∘) ₂; —OP(O)R^(∘)₂; —OP(O)(OR^(∘))₂; SiR^(∘) ₃; —(C₁₋₄ straight or branchedalkylene)O—N(R^(∘))₂; or —(C₁₋₄ straight or branchedalkylene)C(O)O—N(R^(∘))₂, wherein each R^(∘) may be substituted asdefined below and is independently hydrogen, C₁₋₆ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, —CH₂-(5-6 membered heteroaryl ring), or a 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(∘), taken together with their intervening atom(s), form a3-12-membered saturated, partially unsaturated, or aryl mono- orbicyclic ring having 0-4 heteroatoms independently selected fromnitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R^(∘) (or the ring formed by takingtwo independent occurrences of R^(∘) together with their interveningatoms), is independently halogen, —(CH₂)₀₋₂R^(●), -(haloR^(●)),—(CH₂)₀₋₂OH, —(CH₂)₀₋₂OR^(●), —(CH₂)₀₋₂CH(OR^(●))₂; —O(haloR^(●)), —CN,—N₃, —(CH₂)₀₋₂C(O)R^(●), —(CH₂)₀₋₂C(O)OH, —(CH₂)₀₋₂C(O)OR^(●),—(CH₂)₀₋₂SR^(●), —(CH₂)₀₋₂SH, —(CH₂)₀₋₂NH₂, —(CH₂)₀₋₂NHR^(●),—(CH₂)₀₋₂NR^(●) ₂, —NO₂, —SiR^(●) ₃, —OSiR^(●) ₃, —C(O)SR^(●), —(C₁₋₄straight or branched alkylene)C(O)OR^(●), or —SSR^(●) wherein each R^(●)is unsubstituted or where preceded by “halo” is substituted only withone or more halogens, and is independently selected from C₁₋₄ aliphatic,—CH₂Ph, —O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur. Suitable divalent substituents on asaturated carbon atom of R^(∘) include ═O and ═S.

Suitable divalent substituents on a saturated carbon atom of an“optionally substituted” group include the following: ═O, ═S, ═NNR*₂,═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)₂R*, ═NR*, ═NOR*, —O(C(R*₂))₂₋₃₀—, or—S(C(R*₂))₂₋₃S—, wherein each independent occurrence of R* is selectedfrom hydrogen, C₁₋₆ aliphatic which may be substituted as defined below,or an unsubstituted 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur. Suitable divalent substituents that are bound tovicinal substitutable carbons of an “optionally substituted” groupinclude: —O(CR*₂)₂₋₃O—, wherein each independent occurrence of R* isselected from hydrogen, C₁₋₆ aliphatic which may be substituted asdefined below, or an unsubstituted 5-6-membered saturated, partiallyunsaturated, or aryl ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R* include halogen,—R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN, —C(O)OH,—C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein each R^(●) isunsubstituted or where preceded by “halo” is substituted only with oneor more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

Suitable substituents on a substitutable nitrogen of an “optionallysubstituted” group include —R^(†), —NR^(†) ₂, —C(O)R^(†), —C(O)OR^(†),—C(O)C(O)R^(†), —C(O)CH₂C(O)R^(†), —S(O)₂R^(†), —S(O)₂NR^(†) ₂,—C(S)NR^(†) ₂, —C(NH)NR^(†) ₂, or —N(R^(†))S(O)₂R^(†); wherein eachR^(†) is independently hydrogen, C₁₋₆ aliphatic which may be substitutedas defined below, unsubstituted —OPh, or an unsubstituted 5-6-memberedsaturated, partially unsaturated, or aryl ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, or,notwithstanding the definition above, two independent occurrences ofR^(†), taken together with their intervening atom(s) form anunsubstituted 3-12-membered saturated, partially unsaturated, or arylmono- or bicyclic ring having 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

Suitable substituents on the aliphatic group of R^(†) is independentlyhalogen, —R^(●), -(haloR^(●)), —OH, —OR^(●), —O(haloR^(●)), —CN,—C(O)OH, —C(O)OR^(●), —NH₂, —NHR^(●), —NR^(●) ₂, or —NO₂, wherein eachR^(●) is unsubstituted or where preceded by “halo” is substituted onlywith one or more halogens, and is independently C₁₋₄ aliphatic, —CH₂Ph,—O(CH₂)₀₋₁Ph, or a 5-6-membered saturated, partially unsaturated, oraryl ring having 0-4 heteroatoms independently selected from nitrogen,oxygen, or sulfur.

The term “leaving group” refers to an atom (or a group of atoms) withelectron withdrawing ability that can be displaced as a stable species,taking with it the bonding electrons. Examples of suitable leavinggroups include halides and sulfonate esters, including, but not limitedto, triflate, mesylate, tosylate, brosylate, and halides.

The terms “hydrolysable group” and “hydrolysable moiety” refer to afunctional group capable of undergoing hydrolysis, e.g., under basic oracidic conditions. Examples of hydrolysable residues include, withoutlimitation, acid halides, activated carboxylic acids, and variousprotecting groups known in the art (see, for example, “Protective Groupsin Organic Synthesis,” T. W. Greene, P. G. M. Wuts, Wiley-Interscience,1999).

The term “organic residue” defines a carbon containing residue, i.e., aresidue comprising at least one carbon atom, and includes but is notlimited to the carbon-containing groups, residues, or radicals definedhereinabove. Organic residues can contain various heteroatoms, or bebonded to another molecule through a heteroatom, including oxygen,nitrogen, sulfur, phosphorus, or the like. Examples of organic residuesinclude but are not limited alkyl or substituted alkyls, alkoxy orsubstituted alkoxy, mono or di-substituted amino, amide groups, etc.Organic residues can preferably comprise 1 to 18 carbon atoms, 1 to 15,carbon atoms, 1 to 12 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbonatoms, or 1 to 4 carbon atoms. In a further aspect, an organic residuecan comprise 2 to 18 carbon atoms, 2 to 15, carbon atoms, 2 to 12 carbonatoms, 2 to 8 carbon atoms, 2 to 4 carbon atoms, or 2 to 4 carbon atoms.

A very close synonym of the term “residue” is the term “radical,” whichas used in the specification and concluding claims, refers to afragment, group, or substructure of a molecule described herein,regardless of how the molecule is prepared. For example, a2,4-thiazolidinedione radical in a particular compound has the structure

regardless of whether thiazolidinedione is used to prepare the compound.In some embodiments the radical (for example an alkyl) can be furthermodified (i.e., substituted alkyl) by having bonded thereto one or more“substituent radicals.” The number of atoms in a given radical is notcritical to the present invention unless it is indicated to the contraryelsewhere herein.

“Organic radicals,” as the term is defined and used herein, contain oneor more carbon atoms. An organic radical can have, for example, 1-26carbon atoms, 1-18 carbon atoms, 1-12 carbon atoms, 1-8 carbon atoms,1-6 carbon atoms, or 1-4 carbon atoms. In a further aspect, an organicradical can have 2-26 carbon atoms, 2-18 carbon atoms, 2-12 carbonatoms, 2-8 carbon atoms, 2-6 carbon atoms, or 2-4 carbon atoms. Organicradicals often have hydrogen bound to at least some of the carbon atomsof the organic radical. One example, of an organic radical thatcomprises no inorganic atoms is a 5, 6, 7, 8-tetrahydro-2-naphthylradical. In some embodiments, an organic radical can contain 1-10inorganic heteroatoms bound thereto or therein, including halogens,oxygen, sulfur, nitrogen, phosphorus, and the like. Examples of organicradicals include but are not limited to an alkyl, substituted alkyl,cycloalkyl, substituted cycloalkyl, mono-substituted amino,di-substituted amino, acyloxy, cyano, carboxy, carboalkoxy,alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide,substituted dialkylcarboxamide, alkylsulfonyl, alkylsulfinyl, thioalkyl,thiohaloalkyl, alkoxy, substituted alkoxy, haloalkyl, haloalkoxy, aryl,substituted aryl, heteroaryl, heterocyclic, or substituted heterocyclicradicals, wherein the terms are defined elsewhere herein. A fewnon-limiting examples of organic radicals that include heteroatomsinclude alkoxy radicals, trifluoromethoxy radicals, acetoxy radicals,dimethylamino radicals and the like.

“Inorganic radicals,” as the term is defined and used herein, contain nocarbon atoms and therefore comprise only atoms other than carbon.Inorganic radicals comprise bonded combinations of atoms selected fromhydrogen, nitrogen, oxygen, silicon, phosphorus, sulfur, selenium, andhalogens such as fluorine, chlorine, bromine, and iodine, which can bepresent individually or bonded together in their chemically stablecombinations. Inorganic radicals have 10 or fewer, or preferably one tosix or one to four inorganic atoms as listed above bonded together.Examples of inorganic radicals include, but not limited to, amino,hydroxy, halogens, nitro, thiol, sulfate, phosphate, and like commonlyknown inorganic radicals. The inorganic radicals do not have bondedtherein the metallic elements of the periodic table (such as the alkalimetals, alkaline earth metals, transition metals, lanthanide metals, oractinide metals), although such metal ions can sometimes serve as apharmaceutically acceptable cation for anionic inorganic radicals suchas a sulfate, phosphate, or like anionic inorganic radical. Inorganicradicals do not comprise metalloids elements such as boron, aluminum,gallium, germanium, arsenic, tin, lead, or tellurium, or the noble gaselements, unless otherwise specifically indicated elsewhere herein.

Compounds described herein can contain one or more double bonds and,thus, potentially give rise to cis/trans (E/Z) isomers, as well as otherconformational isomers. Unless stated to the contrary, the inventionincludes all such possible isomers, as well as mixtures of such isomers.

Unless stated to the contrary, a formula with chemical bonds shown onlyas solid lines and not as wedges or dashed lines contemplates eachpossible isomer, e.g., each enantiomer and diastereomer, and a mixtureof isomers, such as a racemic or scalemic mixture. Compounds describedherein can contain one or more asymmetric centers and, thus, potentiallygive rise to diastereomers and optical isomers. Unless stated to thecontrary, the present invention includes all such possible diastereomersas well as their racemic mixtures, their substantially pure resolvedenantiomers, all possible geometric isomers, and pharmaceuticallyacceptable salts thereof. Mixtures of stereoisomers, as well as isolatedspecific stereoisomers, are also included. During the course of thesynthetic procedures used to prepare such compounds, or in usingracemization or epimerization procedures known to those skilled in theart, the products of such procedures can be a mixture of stereoisomers.

Many organic compounds exist in optically active forms having theability to rotate the plane of plane-polarized light. In describing anoptically active compound, the prefixes D and L or R and S are used todenote the absolute configuration of the molecule about its chiralcenter(s). The prefixes d and 1 or (+) and (−) are employed to designatethe sign of rotation of plane-polarized light by the compound, with (−)or meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they arenon-superimposable mirror images of one another. A specific stereoisomercan also be referred to as an enantiomer, and a mixture of such isomersis often called an enantiomeric mixture. A 50:50 mixture of enantiomersis referred to as a racemic mixture. Many of the compounds describedherein can have one or more chiral centers and therefore can exist indifferent enantiomeric forms. If desired, a chiral carbon can bedesignated with an asterisk (*). When bonds to the chiral carbon aredepicted as straight lines in the disclosed formulas, it is understoodthat both the (R) and (S) configurations of the chiral carbon, and henceboth enantiomers and mixtures thereof, are embraced within the formula.As is used in the art, when it is desired to specify the absoluteconfiguration about a chiral carbon, one of the bonds to the chiralcarbon can be depicted as a wedge (bonds to atoms above the plane) andthe other can be depicted as a series or wedge of short parallel linesis (bonds to atoms below the plane). The Cahn-Ingold-Prelog system canbe used to assign the (R) or (S) configuration to a chiral carbon.

Compounds described herein comprise atoms in both their natural isotopicabundance and in non-natural abundance. The disclosed compounds can beisotopically-labeled or isotopically-substituted compounds identical tothose described, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number typically found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine,such as ²H, ³H, ¹³C, ¹⁴C, ⁵N, ¹⁸O, ¹⁷O, ³⁵S, ¹⁸F and ³⁶Cl, respectively.Compounds further comprise prodrugs thereof, and pharmaceuticallyacceptable salts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labeled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labeled compounds of the presentinvention and prodrugs thereof can generally be prepared by carrying outthe procedures below, by substituting a readily available isotopicallylabeled reagent for a non-isotopically labeled reagent.

The compounds described in the invention can be present as a solvate. Insome cases, the solvent used to prepare the solvate is an aqueoussolution, and the solvate is then often referred to as a hydrate. Thecompounds can be present as a hydrate, which can be obtained, forexample, by crystallization from a solvent or from aqueous solution. Inthis connection, one, two, three or any arbitrary number of solvate orwater molecules can combine with the compounds according to theinvention to form solvates and hydrates. Unless stated to the contrary,the invention includes all such possible solvates.

The term “co-crystal” means a physical association of two or moremolecules which owe their stability through non-covalent interaction.One or more components of this molecular complex provide a stableframework in the crystalline lattice. In certain instances, the guestmolecules are incorporated in the crystalline lattice as anhydrates orsolvates, see e.g. “Crystal Engineering of the Composition ofPharmaceutical Phases. Do Pharmaceutical Co-crystals Represent a NewPath to Improved Medicines?” Almarasson, O., et al., The Royal Societyof Chemistry, 1889-1896, 2004. Examples of co-crystals includep-toluenesulfonic acid and benzenesulfonic acid.

It is also appreciated that certain compounds described herein can bepresent as an equilibrium of tautomers. For example, ketones with anα-hydrogen can exist in an equilibrium of the keto form and the enolform.

Likewise, amides with an N-hydrogen can exist in an equilibrium of theamide form and the imidic acid form. As another example, pyrazoles canexist in two tautomeric forms, N¹-unsubstituted, 3-A³ andN¹-unsubstituted, 5-A³ as shown below.

Unless stated to the contrary, the invention includes all such possibletautomers.

It is known that chemical substances form solids which are present indifferent states of order which are termed polymorphic forms ormodifications. The different modifications of a polymorphic substancecan differ greatly in their physical properties. The compounds accordingto the invention can be present in different polymorphic forms, with itbeing possible for particular modifications to be metastable. Unlessstated to the contrary, the invention includes all such possiblepolymorphic forms.

In some aspects, a structure of a compound can be represented by aformula:

which is understood to be equivalent to a formula:

wherein n is typically an integer. That is, R^(n) is understood torepresent five independent substituents, R^(n(a)), R^(n(b)), R^(n(c)),R^(n(d)), R^(n(e)). By “independent substituents,” it is meant that eachR substituent can be independently defined. For example, if in oneinstance R^(n(a)) is halogen, then R^(n(b)) is not necessarily halogenin that instance.

Certain materials, compounds, compositions, and components disclosedherein can be obtained commercially or readily synthesized usingtechniques generally known to those of skill in the art. For example,the starting materials and reagents used in preparing the disclosedcompounds and compositions are either available from commercialsuppliers such as Aldrich Chemical Co., (Milwaukee, Wis.), AcrosOrganics (Morris Plains, N.J.), Fisher Scientific (Pittsburgh, Pa.), orSigma (St. Louis, Mo.) or are prepared by methods known to those skilledin the art following procedures set forth in references such as Fieserand Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wileyand Sons, 1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplemental Volumes (Elsevier Science Publishers, 1989); OrganicReactions, Volumes 1-40 (John Wiley and Sons, 1991); March's AdvancedOrganic Chemistry, (John Wiley and Sons, 4th Edition); and Larock'sComprehensive Organic Transformations (VCH Publishers Inc., 1989).

Unless otherwise expressly stated, it is in no way intended that anymethod set forth herein be construed as requiring that its steps beperformed in a specific order. Accordingly, where a method claim doesnot actually recite an order to be followed by its steps or it is nototherwise specifically stated in the claims or descriptions that thesteps are to be limited to a specific order, it is no way intended thatan order be inferred, in any respect. This holds for any possiblenon-express basis for interpretation, including: matters of logic withrespect to arrangement of steps or operational flow; plain meaningderived from grammatical organization or punctuation; and the number ortype of embodiments described in the specification.

Disclosed are the components to be used to prepare the compositions ofthe invention as well as the compositions themselves to be used withinthe methods disclosed herein. These and other materials are disclosedherein, and it is understood that when combinations, subsets,interactions, groups, etc. of these materials are disclosed that whilespecific reference of each various individual and collectivecombinations and permutation of these compounds cannot be explicitlydisclosed, each is specifically contemplated and described herein. Forexample, if a particular compound is disclosed and discussed and anumber of modifications that can be made to a number of moleculesincluding the compounds are discussed, specifically contemplated is eachand every combination and permutation of the compound and themodifications that are possible unless specifically indicated to thecontrary. Thus, if a class of molecules A, B, and C are disclosed aswell as a class of molecules D, E, and F and an example of a combinationmolecule, A-D is disclosed, then even if each is not individuallyrecited each is individually and collectively contemplated meaningcombinations, A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are considereddisclosed. Likewise, any subset or combination of these is alsodisclosed. Thus, for example, the sub-group of A-E, B-F, and C-E wouldbe considered disclosed. This concept applies to all aspects of thisapplication including, but not limited to, steps in methods of makingand using the compositions of the invention. Thus, if there are avariety of additional steps that can be performed it is understood thateach of these additional steps can be performed with any specificembodiment or combination of embodiments of the methods of theinvention.

It is understood that the compositions disclosed herein have certainfunctions. Disclosed herein are certain structural requirements forperforming the disclosed functions, and it is understood that there area variety of structures that can perform the same function that arerelated to the disclosed structures, and that these structures willtypically achieve the same result.

B. Arene C—H Functionalization

As nitrogen-containing aromatic compounds are highly prevalent inpharmaceuticals and natural products, the development of facile routestowards the synthesis of anilines and other nitrogen-containingheterocycles is highly sought after. Anilines are traditionallysynthesized via arene nitration followed by hydrogenation or metalcatalyzed reduction (Belfield et al. (1999) Tetrahedron 55, 11399).Nitration reactions, however, require strongly oxidizing, acidicconditions, which can limit the scope of the reaction due to a lack offunctional group tolerance.

In order to overcome these shortcomings, cross-coupling reactionsinvolving metal catalysts, generally palladium or copper-basedcatalysts, to couple amines with aryl halides or triflates weredeveloped (e.g., Buchwald-Hartwig amination). Despite advancements inligand design and amine nucleophile tolerance, cross-coupling systemscontinue to suffer from several limitations. For example, highly inert,anhydrous conditions are required to prevent catalyst decomposition.Additionally, arenes require prefunctionalization as a halide or atriflate (Surry et al. (2011) Chem. Sci. 2, 27; Hartwig, J. F. (2008)Acc. Chem. Res. 41, 1534). Finally, cross-coupling approaches aregenerally limited by steric hindrance such that amination ortho toanother functional group can be very challenging, resulting in loweryields, as in the ortho-methoxy derivative.

To circumvent the requirement of prefunctionalized arenes, more recentwork has demonstrated the utility of arene C—H functionalization as analternative strategy for the construction of these aryl amines. Currentmethodologies are limited by several factors, includingregioselectivity, necessity of superstoichiometric quantities ofreagents, and, in many cases, non-atom economical oxidants.

The regiochemical outcome of a transition metal-catalyzed arene C—Hfunctionalization is generally dictated by reliance on a preinstalledLewis basic directing group (Matsubara et al. (2014) J. Am. Chem. Soc.136, 646), which results in predominantly ortho-selectivity with respectto that functionality. Buchwald, in 2005, developed an intramoleculararene C—H amination reaction to form carbazoles from 2-acetaminobiphenylderivatives (Tsang et al. (2005) J. Am. Chem. Soc. 127, 14560). Apalladium catalyst was used along with a stoichiometric amount of acopper co-oxidant under aerobic conditions. The amide directedortho-palladation would form the proposed metallocycle, which wouldundergo reductive elimination of the desired carbazole. Other groupshave looked to utilize oxidants such as diacetoxyiodobenzene forintramolecular C—H aminations towards carbazoles (Antonchick et al.(2011) Angew. Chem. Int. Ed. 50, 8605). Methods in which the directinggroup can be removed following the amination have been reported,widening the scope of amination products that can be accessed (Tran etal. (2013) Angew. Chem. Int. Ed. 52, 6043).

Intermolecular arene C—H amination reactions have also been developed,many of which are metal-catalyzed and require directing groups to formortho regioisomers. Shen, in 2010, developed an aerobic copper-mediatedaryl amination reaction (Xu et al. (2014) J. Org. Chem. 79, 4414), inwhich use of a pyridine or pyrimidine directing group facilitated theaddition of phthalimide nucleophiles to arenes with oxygen as a terminaloxidant.

While ortho-selectivity is prevalent, some examples of meta-selectivearene amination reactions have also been reported. Hartwig recentlydemonstrated a sterically controlled intermolecular arene amination(Shrestha et al. (2013) J. Am. Chem. Soc. 135, 8480), using phthalimideas a nucleophile along with diacetoxyiodobenzene as asuperstoichiometric terminal oxidant. While many reactions favoredmeta-functionalization, selectivity overpara-functionalization wasgenerally low. These reactions also required that the arene couplingpartner was the solvent.

In 2011, DeBeof reported a metal-free intermolecular oxidative dual C—Hand N—H bond functionalization reaction (Kantak et al. (2011) J. Am.Chem. Soc. 133, 1960). It was demonstrated that amide derivatives couldadd to various arenes; however, significant excesses of arene wererequired, in some cases even as solvent, to observe the desiredreactivity. Diacetoxyiodobenzene was used as a superstoichiometricoxidant, and microwave irradiation could furnish the functionalizedproducts. The authors proposed that the iodine reagent oxidizes thearene to the aryl radical cation, allowing for addition to the moreelectrophilic ortho- or para-positions on the arene intermediate. Thiswas supported by the observed functionalization occurring at the ortho-and para-positions in roughly 1:1 ratios; however, minor amounts ofmeta-functionalized product were observed but never as the major isomer.DeBeof later demonstrated the use of a gold catalyst along withdiacetoxyiodobenzene as the oxidant to selectively formpara-functionalized products (Marchetti et al. (2015) Org. Lett. 17,258). While this system improved upon previous regioselectivity, itrequired the arene to be used as the solvent, limiting potentialapplicability.

In 2014, Sanford developed a visible light photocatalyzed, [Ir(ppy)₃]mediated system in which N-acyloxyphthalimide could form nitrogencentered radicals and subsequently add to arenes and heteroarenes (Allenet al. (2014) J. Am. Chem. Soc. 136, 5607). Many of the substrates wereortho-functionalized; however, Sanford was able to demonstratemeta-selectivity with pyridine derivatives. It is believed that visiblelight excites the iridium catalyst, which induces a SET process,cleaving the N—O bond of the acyloxyphthalimide to generate a nitrogencentered radical that can add to the arene. While no additional oxidantswere required for this system, the authors reported using 10 equivalentsof the arene as well as a prefunctionalized phthalimide.

Use of electrooxidative conditions to facilitate arene coupling can beeffective but also problematic due to undesirable oxidation offunctional groups in the substrates. Yoshida demonstrated the use ofprotected imidazoles in an electrooxidative coupling with both aromaticand benzylic electrophiles (Morofuji et al. (2014) J. Am. Chem. Soc.136, 4496). Protection of the imidazole or benzimidazole nucleophileprevented overoxidation of the imidazole products, which aresusceptibile to electrochemical oxidation; however, treatment with baseafter the reaction was required to cleave the mesylate group.

To date, many ortho-selective aryl amination reactions have beendeveloped; however, some meta-selective examples have also beenreported. Furthermore, use of stoichiometric oxidants results in pooratom economy, demonstrating how use of molecular oxygen as an oxidantcan be appealing in terms of minimizing waste. Excess arene (Brachet etal. (2014) Advance Article; Prier et al. (2013) Chem. Rev. 113, 5322),even in the form of the reaction solvent, often required to achievesynthetically useful yields, limiting applicability to easily attainablesubstrates.

Herein, an oxidative method of arene functionalization in whichnucleophiles including, but not limited to, amines and halides can beadded to arenes using an organic catalyst, i.e., an acridiniumphotocatalyst, where dioxygen (O₂) is the terminal oxidant is disclosed.This strategy constitutes a facile synthesis of para-substitutedanilines via an arene C—H functionalization. It has been observed that apersistent radical additive or a precursor to an in situ generatedpersistent radical may improve chemical yields; however, addition ofsuch an exogenous additive is not required under modified conditions.Unlike previous examples of direct aryl amination reported in theliterature, this method does not stipulate a significant excess ofeither arene or amine. Anilines may be synthesized directly via additionof ammonia in the form of simple ammonium salts. Additionally,chlorinated and fluorinated arenes were detected when halide salts wereemployed, indicating that arene functionalization is feasible throughthis method with other classes of nucleophiles. This method does notrely on a Lewis basic substituent for regiochemical differentiation;thus, a greater variety of arene substitution patterns can be accessed.Lastly, the use of dioxygen as a reagent and an organic photocatalyst isan attractive alternative to the more expensive and environmentallynoxious oxidants and transition metals employed in other methodologies.

C. Photoredox Chemistry

Given that many organic compounds do not absorb in the visible region ofthe electromagnetic spectrum, various reactions have been developed thatinstead use ultraviolet light, which these molecules can absorb. Toharness visible light instead, metal complexes such as [Ru(byp)₃]²⁺ and[Ir(ppy)₃] (Pirer et al. (2013) Chem. Rev. 113, 5322) and organic dyessuch as methylene blue and eosin Y (Nicewicz and Nguyen (2014) ACSCatal. 4, 355), have been examined.

When looking to employ oxidative photoredox chemistry, identifying anappropriate catalyst can be challenging. For example, photocatalystssuch as [Ru(byp)_(3]) ²⁺ (E_(1/2) ^(red)*=+0.77 V vs. SCE) are capableof oxidizing electron-rich alkenes but not aliphatic alkenes. Similarly,eosin Y (E_(1/2) ^(red)*=+0.79 V vs. SCE) is able to oxidize compoundsin the same range. While ligand modification on various metalphotocatalysts can facilitate oxidation of less oxidizable substrates,such derivatives generally do not possess oxidation potentials highenough to react with disubstituted alkenes.

The use of Fukuzumi's catalyst (Mes-Acr-MeBF₄) in anti-Markovnikovhydroetherification (Hamilton and Nicewicz (2012) J. Am. Chem. Soc. 134,18577), hydroamination (Nguyen and Nicewicz (2013) J. Am. Chem. Soc.135, 9588), and hydroacetoxylation (Perkowshi and Nicewicz (2013)J. Am.Chem. Soc. 135, 10334) has been previously demonstrated. In theintermolecular hydroamination reactions, several amides, sulfonimides,and nitrogen-containing heterocycles such as pyrazoles and triazoles,were used to functionalize alkenes (Nguyen et al. (2014) Angew. Chem.Int. Ed. 53, 6198). It has been theorized that after excitation byvisible light (450 nm LEDs), Fukuzumi's catalyst can undergo singleelectron transfer (SET) from the olefin, generating a radical cation.Subsequent nucleophilic addition and H-atom donation affords theanti-Markovnikov adduct. This regioselective functionalization arisesfrom the formation of the more stable benzylic radical.

In addition to alkenes, the mesityl acridinium catalyst has also beenshown to oxidize sufficiently electron-rich arenes (Ohkuba et al. (2011)Chem. Sci. 2, 715). Here, the bromination of various electron-richarenes using Fukuzumi's catalyst and hydrobromic acid under aerobicconditions was reported. Several methoxy-substituted arenes produced thedesired bromination product in high yields in as little as 20 minutes,although some less electron-rich arenes required up to 16 hours forquantitative conversion. For methyl-substituted arenes, conversion ofthe starting material was still quantitative; however, the yields weresignificantly lower due to competing benzylic oxidation. It was proposedthat the photocatalyst is excited, which can oxidize an electron-richarene to a radical cation. Bromine addition followed by oxidationaffords the corresponding arene derivative. This research was laterextended to chlorination reactions with a similar aerobic system (Ohkubuet al. (2013) Res. Chem. Intermed. 39, 205). Highly oxidizable arenessuch as trimethoxybenzenes furnished the chlorinated products; however,they were obtained in low yields (generally less than 25%).

D. Substituted Arenes

In one aspect, substituted arenes are disclosed. In a further aspect,the arene is para-substituted. In a still further aspect, the arene isortho-substituted. In yet a further aspect, the arene is both para- andortho-substituted.

It is contemplated that each disclosed derivative can be optionallyfurther substituted. It is also contemplated that any one or morederivative can be optionally omitted from the invention. It isunderstood that a disclosed compound can be provided by the disclosedmethods.

1. Structure

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl; wherein Z is selected from halogen, —CN, —NH₂, —OH, C1-C8alkenyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, arylamino, diarylamino, C1-C8 alkarylamino,—NNR⁴, —OC(═O)R⁵, and Ar¹; wherein R⁴ is selected from hydrogen andC1-C8 alkyl; wherein R⁵ is selected from C1-C8 alkyl; and wherein Ar¹ isa 3- to 6-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from halogen and C1-C8 alkyl. In a furtheraspect, the electron donating group is selected from —OH, —SH, —NH₂,C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8 silyloxy, C1-C8alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, —OAr²,and Ar²; wherein each of R⁶ and R⁷ is independently selected from C1-C8alkyl; and wherein Ar² is selected from aryl and heteroaryl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen and C1-C8 alkyl. In a still further aspect, the electrondonating group is selected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,—OC(═O)R⁶, —NHC(═O)R⁷, and Ar²; wherein each of R⁶ and R⁷ isindependently selected from C1-C8 alkyl; and wherein Ar² is selectedfrom aryl and heteroaryl and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen and C1-C8 alkyl.

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl; or wherein each of Q² and Q⁴ is CR² and wherein eachoccurrence of R² are optionally covalently bonded and, together with theintermediate atoms, comprise a 5- to 6-membered cycle or heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); wherein Zis selected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8 alkoxy,C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; and wherein Ar¹ is a 3- to 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen and C1-C8 alkyl. In a further aspect, the electron donatinggroup is selected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8thioalkoxy, C1-C8 silyloxy, C1-C8 alkylamino, (C1-C8)(C1-C8)dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, —OAr², and Ar²; wherein each of R⁶and R⁷ is independently selected from C1-C8 alkyl; and wherein Ar² isselected from aryl and heteroaryl and substituted with 0, 1, 2, or 3groups independently selected from halogen and C1-C8 alkyl. In a stillfurther aspect, the electron donating group is selected from —OH, —SH,—NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, and Ar²; whereineach of R⁶ and R⁷ is independently selected from C1-C8 alkyl; andwherein Ar² is selected from aryl and heteroaryl and substituted with 0,1, 2, or 3 groups independently selected from halogen and C1-C8 alkyl.

In one aspect, disclosed are compounds having a structure represented bya formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle substituted with 0, 1, 2, or 3groups independently selected from halogen, C1-C8 alkyl, C1-C8 alkoxy,and —C(═O)NR^(3a)R^(3b); wherein each of R^(3a) and R^(3b) isindependently selected from hydrogen and C1-C4 alkyl; wherein Z isselected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8 alkoxy,C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; and wherein Ar¹ is a 3- to 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen and C1-C8 alkyl. In a further aspect, the electron donatinggroup is selected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8thioalkoxy, C1-C8 silyloxy, C1-C8 alkylamino, (C1-C8)(C1-C8)dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, —OAr², and Ar²; wherein each of R⁶and R⁷ is independently selected from C1-C8 alkyl; and wherein Ar² isselected from aryl and heteroaryl and substituted with 0, 1, 2, or 3groups independently selected from halogen and C1-C8 alkyl. In a stillfurther aspect, the electron donating group is selected from —OH, —SH,—NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, and Ar²; whereineach of R⁶ and R⁷ is independently selected from C1-C8 alkyl; andwherein Ar² is selected from aryl and heteroaryl and substituted with 0,1, 2, or 3 groups independently selected from halogen and C1-C8 alkyl.

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wherein A is selected from CR¹²R^(12b), O, S, and NR¹³; wherein each ofR^(12a), R^(12b), and R¹³, when present, is independently selected fromhydrogen and C1-C4 alkyl; and wherein each of R^(11a) and R^(11b) isindependently selected from hydrogen and C1-C4 alkyl.

In a further aspect, a compound has a structure represented by a formulaselected from:

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In a further aspect, a compound has a structure represented by aformula:

wherein each of Q⁵, Q⁶, Q⁷, and Q⁸ is independently selected from N andCR¹⁴; and wherein each occurrence of R¹⁴ is independently selected fromhydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(O)NR^(3a)R^(3b).

In a further aspect, a compound has a structure represented by a formulaselected from:

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In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by aformula:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by aformula:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by aformula:

In a further aspect, a compound has a structure represented by aformula:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by aformula:

In a further aspect, a compound has a structure represented by aformula:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by aformula:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by aformula:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by a formulaselected from:

wherein A is selected from CR¹²R^(12b), O, S, and NR¹³; wherein each ofR^(12a), R^(12b), and R¹³, when present, is independently selected fromhydrogen and C1-C4 alkyl; and wherein each of R^(11a) and R^(11b) isindependently selected from hydrogen and C1-C4 alkyl.

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by a formulaselected from:

wherein each of Q⁵, Q⁶, Q⁷, and Q⁸ is independently selected from N andCR¹⁴; and wherein each occurrence of R¹⁴ is independently selected fromhydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(O)NR^(3a)R^(3b).

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by a formulaselected from:

In a further aspect, a compound has a structure represented by a formulaselected from:

a. A Groups

In one aspect, A is selected from CR^(12a)R^(12b), O, S, and NR¹³. In afurther aspect, A, when present, is selected from O, S, and NR¹³. In astill further aspect, A is selected from S and NR¹³. In yet a furtheraspect, A is selected from O and NR¹³. In an even further aspect, A isNR¹³. In a still further aspect, A is CR^(12a)R^(12b). In yet a furtheraspect, A is O. In an even further aspect, A is S.

b. E Groups

In one aspect, E is an electron donating group. Exemplary electrondonating groups are well known by those skilled in the art and include,but are not limited to, alkyl, alcohol, thioalcohol, alkoxy, thioalkoxy,silyloxy, amine, ester, amide, and aryl groups.

In a further aspect, the electron donating group is selected from —OH,—SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8 silyloxy,C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷,—OAr², and Ar². In a still further aspect, the electron donating groupis selected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C4thioalkoxy, C1-C4 silyloxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, —OAr², and Ar².

In a further aspect, the electron donating group is selected from —OH,—SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, and Ar².In a still further aspect, the electron donating group is selected from—OH, —SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C4 thioalkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, and Ar².

In a further aspect, the electron donating group is selected from —OH,—SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶, and —NHC(═O)R⁷. In astill further aspect, the electron donating group is selected from —OH,—SH, —NH₂, C1-C8 alkyl, C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, —OC(═O)R⁶, and —NHC(═O)R⁷. Inyet a further aspect, the electron donating group is selected from —OH,—SH, —NH₂, methyl, ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —OCH(CH₃)₂, —SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)(CH₂CH₃),—N(CH₃)(CH₂CH₂CH₃), —N(CH₃)(CH(CH₃)₂), —N(CH₂CH₃)₂,—N(CH₂CH₃)(CH₂CH₂CH₃), —N(CH₂CH₃)(CH(CH₃)₂), —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₃)(CH(CH₃)₂), —N(CH(CH₃)₂)₂, —OC(═O)R⁶, and —NHC(═O)R⁷. In aneven further aspect, the electron donating group is selected from —OH,—SH, —NH₂, methyl, ethyl, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, —N(CH₃)(CH₂CH₃), —N(CH₂CH₃)₂, —OC(═O)R⁶, and—NHC(═O)R⁷. In a still further aspect, the electron donating group isselected from —OH, —SH, —NH₂, methyl, —OCH₃, —SCH₃, —NHCH₃, —N(CH₃)₂,—OC(═O)R⁶, and —NHC(═O)R⁷.

In a further aspect, the electron donating group is a C1-C8 silyloxy. Ina still further aspect, the electron donating group is selected fromtrimethylsilyloxy, triisopropylsilyloxy, and tert-butyldimethylsilyloxy.In yet a further aspect, the electron donating group is selected fromtrimethylsilyloxy and triisopropylsilyloxy. In an even further aspect,the electron donating group is tert-butyldimethylsilyloxy. In a stillfurther aspect, the electron donating group is triisopropylsilyloxy. Inyet a further aspect, the electron donating group is trimethylsilyloxy.

In a further aspect, the electron donating group is selected from —OH,—SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8alkylamino, and (C1-C8)(C1-C8) dialkylamino. In a still further aspect,the electron donating group is selected from —OH, —SH, —NH₂, C1-C8alkyl, C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4 alkylamino, and(C1-C4)(C1-C4) dialkylamino. In yet a further aspect, the electrondonating group is selected from —OH, —SH, —NH₂, methyl, ethyl, n-propyl,iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, —SCH₃, —SCH₂CH₃,—SCH₂CH₂CH₃, —SCH(CH₃)₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂,—N(CH₃)₂, —N(CH₃)(CH₂CH₃), —N(CH₃)(CH₂CH₂CH₃), —N(CH₃)(CH(CH₃)₂),—N(CH₂CH₃)₂, —N(CH₂CH₃)(CH₂CH₂CH₃), —N(CH₂CH₃)(CH(CH₃)₂),—N(CH₂CH₂CH₃)₂, —N(CH₂CH₂CH₃)(CH(CH₃)₂), and —N(CH(CH₃)₂)₂. In an evenfurther aspect, the electron donating group is selected from —OH, —SH,—NH₂, methyl, ethyl, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —NHCH₃,—NHCH₂CH₃, —N(CH₃)₂, —N(CH₃)(CH₂CH₃), and —N(CH₂CH₃)₂. In a stillfurther aspect, the electron donating group is selected from —OH, —SH,—NH₂, methyl, —OCH₃, —SCH₃, —NHCH₃, and —N(CH₃)₂.

In a further aspect, the electron donating group is selected from —OH,—SH, —NH₂, —OC(═O)R⁶, —NHC(═O)R⁷, —OAr², and Ar². In a still furtheraspect, the electron donating group is selected from —OC(═O)R⁶,—NHC(═O)R⁷, —OAr², and Ar². In yet a further aspect, the electrondonating group is —OAr².

In a further aspect, the electron donating group is selected from —OH,—SH, —NH₂, —OC(═O)R⁶, —NHC(═O)R⁷, and Ar². In a still further aspect,the electron donating group is selected from —OC(═O)R⁶, —NHC(═O)R⁷, andAr². In yet a further aspect, the electron donating group is selectedfrom —OC(═O)R⁶ and —NHC(═O)R⁷. In an even further aspect, the electrondonating group is —OC(═O)R⁶. In a still further aspect, the electrondonating group is —NHC(═O)R⁷. In yet a further aspect, the electrondonating group is Ar².

In a further aspect, the electron donating group is selected from C1-C8alkyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino, and(C1-C8)(C1-C8) dialkylamino. In a still further aspect, the electrondonating group is selected from C1-C8 alkyl, C1-C4 alkoxy, C1-C4thioalkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. In yet afurther aspect, the electron donating group is selected from methyl,ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,—SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)₂, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)(CH₂CH₃),—N(CH₃)(CH₂CH₂CH₃), —N(CH₃)(CH(CH₃)₂), —N(CH₂CH₃)₂,—N(CH₂CH₃)(CH₂CH₂CH₃), —N(CH₂CH₃)(CH(CH₃)₂), —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₃)(CH(CH₃)₂), and —N(CH(CH₃)₂)₂. In an even further aspect,the electron donating group is selected from methyl, ethyl, —OCH₃,—OCH₂CH₃, —SCH₃, —SCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₃)(CH₂CH₃),and —N(CH₂CH₃)₂. In a still further aspect, the electron donating groupis selected from methyl, —OCH₃, —SCH₃, —NHCH₃, and —N(CH₃)₂.

In a further aspect, the electron donating group is selected from —OH,—SH, and —NH₂. In a still further aspect, the electron donating group isselected from —OH and —SH. In yet a further aspect, the electrondonating group is selected from —OH and —NH₂. In an even further aspect,the electron donating group is selected from —SH and —NH₂. In a stillfurther aspect, the electron donating group is —OH. In yet a furtheraspect, the electron donating group is —SH. In an even further aspect,the electron donating group is NH₂.

c. Z Groups

In one aspect, Z is selected from halogen, —CN, —NH₂, —OH, C1-C8alkenyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, arylamino, diarylamino, C1-C8 alkarylamino,—NNR⁴, —OC(═O)R⁵, and Ar¹. In a further aspect, Z is selected fromhalogen, —CN, —NH₂, —OH, C1-C4 alkenyl, C1-C4 alkoxy, C1-C4 thioalkoxy,C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, arylamino, diarylamino,C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Art.

In a further aspect, Z is selected from halogen, —CN, —NH₂, —OH, C1-C8alkenyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, arylamino, diarylamino, and C1-C8alkarylamino. In a still further aspect, Z is selected from halogen,—CN, —NH₂, —OH, C1-C4 alkenyl, C1-C4 alkoxy, C1-C4 thioalkoxy, C1-C4alkylamino, (C1-C4)(C1-C4) dialkylamino, arylamino, diarylamino, andC1-C4 alkarylamino. In yet a further aspect, Z is selected fromfluorine, chlorine, —CN, —NH₂, —OH, ethenyl, propenyl, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —OCH(CH₃)₂, —SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)(CH₂CH₃),—N(CH₃)(CH₂CH₂CH₃), —N(CH₃)(CH(CH₃)₂), —N(CH₂CH₃)₂,—N(CH₂CH₃)(CH₂CH₂CH₃), —N(CH₂CH₃)(CH(CH₃)₂), —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₃)(CH(CH₃)₂), —N(CH(CH₃)₂)₂, —NHAr¹, —N(Ar¹)₂, —N(CH₃)Ar¹,—N(CH₂CH₃)Ar¹, —N(CH₂CH₂CH₃)Ar¹, and —N(CH(CH₃)₂)Ar¹. In an even furtheraspect, Z is selected from fluorine, chlorine, —CN, —NH₂, —OH, ethenyl,—OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₃)(CH₂CH₃), —NHAr¹, —N(Ar¹)₂, —N(CH₃)Ar¹, and —N(CH₂CH₃)Ar¹. In astill further aspect, Z is selected from fluorine, chlorine, —CN, —NH₂,—OH, —OCH₃, —SCH₃, —NHCH₃, —N(CH₃)₂, —NHAr¹, —N(Ar¹)₂, and —N(CH₃)Ar¹.

In a further aspect, Z is selected from C1-C8 alkenyl, C1-C8 alkoxy,C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, and C1-C8 alkarylamino. In a still furtheraspect, Z is selected from C1-C4 alkenyl, C1-C4 alkoxy, C1-C4thioalkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, arylamino,diarylamino, and C1-C4 alkarylamino. In yet a further aspect, Z isselected from ethenyl, propenyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,—OCH(CH₃)₂, —SCH₃, —SCH₂CH₃, —SCH₂CH₂CH₃, —SCH(CH₃)₂, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)(CH₂CH₃),—N(CH₃)(CH₂CH₂CH₃), —N(CH₃)(CH(CH₃)₂), —N(CH₂CH₃)₂,—N(CH₂CH₃)(CH₂CH₂CH₃), —N(CH₂CH₃)(CH(CH₃)₂), —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₃)(CH(CH₃)₂), —N(CH(CH₃)₂)₂, —NHAr¹, —N(Ar¹)₂, —N(CH₃)Ar¹,—N(CH₂CH₃)Ar¹, —N(CH₂CH₂CH₃)Ar¹, and —N(CH(CH₃)₂)Ar¹. In an even furtheraspect, Z is selected from ethenyl, —OCH₃, —OCH₂CH₃, —SCH₃, —SCH₂CH₃,—NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₃)(CH₂CH₃), —NHAr¹, —N(Ar¹)₂,—N(CH₃)Ar¹, and —N(CH₂CH₃)Ar¹. In a still further aspect, Z is selectedfrom —OCH₃, —SCH₃, —NHCH₃, —N(CH₃)₂, —NHAr¹, —N(Ar¹)₂, and —N(CH₃)Ar¹.

In a further aspect, Z is selected from halogen, —CN, —NH₂, —OH, —NNR⁴,—OC(═O)R⁵, and Ar¹. In a still further aspect, Z is selected fromfluorine, chlorine, —CN, —NH₂, —OH, —NNR⁴, —OC(═O)R⁵, and Ar¹. In yet afurther aspect, Z is selected from —NNR⁴, —OC(═O)R⁵, and Ar¹. In an evenfurther aspect, Z is selected from —OC(═O)R⁵ and Ar¹. In a still furtheraspect, Z is selected from —NNR⁴ and —OC(═O)R⁵. In yet a further aspect,Z is selected from —NNR⁴ and Ar¹. In an even further aspect, Z is —NNR⁴.In a still further aspect, Z is —OC(═O)R⁵. In yet a further aspect, Z isAr¹.

In a further aspect, Z is selected from —CN, —NH₂, and —OH. In a stillfurther aspect, Z is selected from —NH₂, and —OH. In yet a furtheraspect, Z is selected from —CN and —NH₂. In an even further aspect, Z isselected from —CN and —OH. In a still further aspect, Z is —CN. In yet afurther aspect, Z is —NH₂. In an even further aspect, Z is —OH.

In a further aspect, Z is selected from C1-C8 alkylamino, (C1-C8)(C1-C8)dialkylamino, arylamino, diarylamino, and C1-C8 alkarylamino. In a stillfurther aspect, Z is selected from C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, arylamino, diarylamino, C1-C4 alkarylamino.

In a further aspect, Z is a halogen. In a still further aspect, Z isselected from fluorine and chlorine. In yet a further aspect, Z ischlorine. In an even further aspect, Z is fluorine.

d. Q¹, Q², Q³, and Q⁴ Groups

In one aspect, each of Q¹ and Q³ is independently selected from N andCR¹ and each of Q² and Q⁴ is independently selected from N and CR². In afurther aspect, at least one of Q¹, Q², Q³, and Q⁴ is N. In a stillfurther aspect, at least one of Q¹ and Q³ is N. In yet a further aspect,at least one of Q² and Q⁴ is N.

In one aspect, each of Q¹ and Q³ is independently selected from N andCR¹ and each of Q² and Q⁴ is CR². In a further aspect, each of Q¹ and Q³is CR¹ and each of Q² and Q⁴ is CR².

In a further aspect, each of Q¹ and Q³ is independently selected from Nand CR¹. In a still further aspect, Q¹ is N and Q³ is CR¹. In yet afurther aspect, Q¹ is CR¹ and Q³ is N. In an even further aspect, eachof Q¹ and Q³ is CR¹. In a still further aspect, each of Q¹ and Q³ is N.

In a further aspect, each of Q² and Q⁴ is independently selected from Nand CR². In a still further aspect, Q² is N and Q⁴ is CR². In yet afurther aspect, Q² is CR² and Q⁴ is N. In an even further aspect, eachof Q² and Q⁴ is CR². In a still further aspect, each of Q² and Q⁴ is N.

e. Q⁵, Q⁶, Q⁷, and Q⁸ Groups

In one aspect, each of Q⁵, Q⁶, Q⁷, and Q⁸ is independently selected fromN and CR¹⁴. In a further aspect, at least one of Q⁵, Q⁶, Q⁷, and Q⁸ isN. In a still further aspect, at least one of Q⁵, Q⁶, Q⁷, and Q⁸ isCR¹⁴. In yet a further aspect, each of Q⁵, Q⁶, Q⁷, and Q⁸ is CR⁴.

f. R¹ and R² Groups

In one aspect, each occurrence of R¹ and R² is independently selectedfrom hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b), or R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cycleor heterocycle having 0, 1, or 2 heteroatoms and substituted with 0, 1,2, or 3 groups independently selected from halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b). In a further aspect, each occurrence ofR¹ and R² is hydrogen.

In one aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 5- to 6-memberedcycle or heterocycle substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In a further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered cycle or heterocycle substituted with 0, 1,2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4alkoxy, and —C(═O)NR^(3a)R^(3b). In a still further aspect, eachoccurrence of R² is optionally covalently bonded and, together with theintermediate atoms, comprise a 5- to 6-membered cycle or heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In yet afurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 5- to 6-memberedcycle or heterocycle substituted with 0, 1, 2, or 3 groups independentlyselected from fluorine, chlorine, methyl, ethyl, —OCH₃, —OCH₂CH₃, and—C(═O)NR^(3a)R^(3b). In an even further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered cycle or heterocycle substituted with 0, 1,2, or 3 groups independently selected from fluorine, chlorine, methyl,—OCH₃, and —C(═O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R¹ and R² is independentlyselected from hydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R¹and R² is independently selected from hydrogen, halogen, C1-C4 alkyl,C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet a further aspect, eachoccurrence of R¹ and R² is independently selected from hydrogen,fluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, each occurrence of R¹ and R² is independently selectedfrom hydrogen, fluorine, chlorine, methyl, ethyl, —OCH₃, —OCH₂CH₃, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R¹and R² is independently selected from hydrogen, fluorine, chlorine,methyl, —OCH₃, and —C(O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R¹ and R² is independentlyselected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R¹and R² is independently selected from hydrogen, C1-C4 alkyl, C1-C4alkoxy, and —C(═O)NR^(3a)R^(3b). In yet a further aspect, eachoccurrence of R¹ and R² is independently selected from hydrogen, methyl,ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,and —C(═O)NR^(3a)R^(3b). In an even further aspect, each occurrence ofR¹ and R² is independently selected from hydrogen, methyl, ethyl, —OCH₃,—OCH₂CH₃, and —C(═O)NR^(3a)R^(3b). In a still further aspect, eachoccurrence of R¹ and R² is independently selected from hydrogen, methyl,—OCH₃, and —C(O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R¹ and R² is independentlyselected from hydrogen, C1-C8 alkyl, and C1-C8 alkoxy. In a stillfurther aspect, each occurrence of R¹ and R² is independently selectedfrom hydrogen, C1-C4 alkyl, and C1-C4 alkoxy. In yet a further aspect,each occurrence of R¹ and R² is independently selected from hydrogen,methyl, ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, and—OCH(CH₃)₂. In an even further aspect, each occurrence of R¹ and R² isindependently selected from hydrogen, methyl, ethyl, —OCH₃, and—OCH₂CH₃. In a still further aspect, each occurrence of R¹ and R² isindependently selected from hydrogen, methyl, and —OCH₃.

In a further aspect, each occurrence of R¹ and R² is independentlyselected from hydrogen and halogen. In a still further aspect, eachoccurrence of R¹ and R² is independently selected from hydrogen,fluorine, and chlorine. In yet a further aspect, each occurrence of R¹and R² is independently selected from hydrogen and chlorine. In a stillfurther aspect, each occurrence of R¹ and R² is independently selectedfrom hydrogen and fluorine.

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cycleor heterocycle having 0, 1, or 2 heteroatoms and substituted with 0, 1,2, or 3 groups independently selected from halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b). In a still further aspect, R¹ and R²are optionally covalently bonded and, together with the intermediateatoms, comprise a 5- to 6-membered cycle or heterocycle having 0, 1, or2 heteroatoms and substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, C1-C4 alkyl, C1-C4 alkoxy, and—C(═O)NR^(3a)R^(3b). In yet a further aspect, R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 5- to 6-membered cycle orheterocycle having 0, 1, or 2 heteroatoms and substituted with 0, 1, 2,or 3 groups independently selected from fluorine, chlorine, methyl,ethyl, —OCH₃, —OCH₂CH₃, and —C(═O)NR^(3a)R^(3b). In a still furtheraspect, R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 5-to 6-membered cycle or heterocyclehaving 0, 1, or 2 heteroatoms and substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, —OCH₃, and—C(═O)NR^(3a)R^(3b).

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cycleor heterocycle having 0, 1, or 2 heteroatoms and substituted with 0, 1,2, or 3 groups independently selected from halogen, C1-C8 alkyl, C1-C8alkoxy, —(C1-C8 alkyl)-C02-(C1-C4 alkyl), and —C(═O)NR^(3a)R^(3b). In astill further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cycleor heterocycle having 0, 1, or 2 heteroatoms and substituted with 0, 1,2, or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4alkoxy, —(C1-C4 alkyl)-CO₂—(C1-C2 alkyl), and —C(═O)NR^(3a)R^(3b). Inyet a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cycleor heterocycle having 0, 1, or 2 heteroatoms and substituted with 0, 1,2, or 3 groups independently selected from fluorine, chlorine, methyl,ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,—CH(CH₃)CO₂CH₂CH₂CH₃, —CH(CH₃)CO₂CH₃, and —C(═O)NR^(3a)R^(3b). In aneven further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cycleor heterocycle having 0, 1, or 2 heteroatoms and substituted with 0, 1,2, or 3 groups independently selected from fluorine, chlorine, methyl,ethyl, —OCH₃, —OCH₂CH₃, —CH(CH₃)CO₂CH₃, and —C(═O)NR^(3a)R^(3b). In astill further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cycleor heterocycle having 0, 1, or 2 heteroatoms and substituted with 0, 1,2, or 3 groups independently selected from fluorine, chlorine, methyl,—OCH₃, —CH(CH₃)CO₂CH₃, and —C(═O)NR^(3a)R^(3b).

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cycleor heterocycle having 0, 1, or 2 heteroatoms and substituted with 0, 1,or 2 groups independently selected from halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b). In a still further aspect, R¹ and R²are optionally covalently bonded and, together with the intermediateatoms, comprise a 5- to 6-membered cycle or heterocycle having 0, 1, or2 heteroatoms and substituted with 0 or 1 group selected from halogen,C1-C8 alkyl, C1-C8 alkoxy, and —C(O)NR^(3a)R^(3b). In yet a furtheraspect, R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 5- to 6-membered cycle or heterocyclehaving 0, 1, or 2 heteroatoms and monosubstituted with a group selectedfrom halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In aneven further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cycleor heterocycle having 0, 1, or 2 heteroatoms and unsubstituted.

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a stillfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 5- to 6-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C4 alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet afurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 5- to 6-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 5- to 6-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, —OCH₃, —OCH₂CH₃, and—C(═O)NR^(3a)R^(3b). In a still further aspect, R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, —OCH₃, and—C(O)NR^(3a)R^(3b).

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-membered cyclesubstituted with 0, 1, or 2 groups independently selected from halogen,C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a still furtheraspect, R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 5- to 6-membered cycle substitutedwith 0 or 1 group selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In yet a further aspect, R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle monosubstituted with a group selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 5- to 6-membered unsubstitutedcycle.

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a stillfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 5-membered cycle substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, C1-C4alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet a further aspect,R¹ and R² are optionally covalently bonded and, together with theintermediate atoms, comprise a 5-membered cycle substituted with 0, 1,2, or 3 groups independently selected from fluorine, chlorine, methyl,ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,and —C(═O)NR^(3a)R^(3b). In an even further aspect, R¹ and R² areoptionally covalently bonded and, together with the intermediate atoms,comprise a 5-membered cycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl, —OCH₃,—OCH₂CH₃, and —C(═O)NR^(3a)R^(3b). In a still further aspect, R¹ and R²are optionally covalently bonded and, together with the intermediateatoms, comprise a 5-membered cycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, —OCH₃, and—C(═O)NR^(3a)R^(3b).

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5-membered cyclesubstituted with 0, 1, or 2 groups independently selected from halogen,C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a still furtheraspect, R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 5-membered cycle substituted with 0or 1 group selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In yet a further aspect, R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5-membered cycle monosubstituted with a group selected from halogen,C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In an even furtheraspect, R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 5-membered unsubstituted cycle.

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 6-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a stillfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered cycle substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, C1-C4alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet a further aspect,R¹ and R² are optionally covalently bonded and, together with theintermediate atoms, comprise a 6-membered cycle substituted with 0, 1,2, or 3 groups independently selected from fluorine, chlorine, methyl,ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,and —C(═O)NR^(3a)R^(3b). In an even further aspect, R¹ and R² areoptionally covalently bonded and, together with the intermediate atoms,comprise a 6-membered cycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl, —OCH₃,—OCH₂CH₃, and —C(═O)NR^(3a)R^(3b). In a still further aspect, R¹ and R²are optionally covalently bonded and, together with the intermediateatoms, comprise a 6-membered cycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, —OCH₃, and—C(═O)NR^(3a)R^(3b).

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 6-membered cyclesubstituted with 0, 1, or 2 groups independently selected from halogen,C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a still furtheraspect, R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 6-membered cycle substituted with 0or 1 group selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In yet a further aspect, R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a6-membered cycle monosubstituted with a group selected from halogen,C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In an even furtheraspect, R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 6-membered unsubstituted cycle.

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-memberedheterocycle having 0, 1, or 2 heteroatoms and substituted with 0, 1, 2,or 3 groups independently selected from halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b). In a still further aspect, R¹ and R²are optionally covalently bonded and, together with the intermediateatoms, comprise a 5- to 6-membered heterocycle substituted with 0, 1, 2,or 3 groups independently selected from halogen, C1-C4 alkyl, C1-C4alkoxy, and —C(═O)NR^(3a)R^(3b). In yet a further aspect, R¹ and R² areoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered heterocycle substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, methyl, ethyl,n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and—C(═O)NR^(3a)R^(3b). In an even further aspect, R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl, —OCH₃,—OCH₂CH₃, and —C(═O)NR^(3a)R^(3b). In a still further aspect, R¹ and R²are optionally covalently bonded and, together with the intermediateatoms, comprise a 5- to 6-membered heterocycle substituted with 0, 1, 2,or 3 groups independently selected from fluorine, chlorine, methyl,—OCH₃, and —C(═O)NR^(3a)R^(3b).

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-memberedheterocycle substituted with 0, 1, or 2 groups independently selectedfrom halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In astill further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-memberedheterocycle substituted with 0 or 1 group selected from halogen, C1-C8alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet a further aspect,R¹ and R² are optionally covalently bonded and, together with theintermediate atoms, comprise a 5- to 6-membered heterocyclemonosubstituted with a group selected from halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b). In an even further aspect, R¹ and R²are optionally covalently bonded and, together with the intermediateatoms, comprise a 5- to 6-membered unsubstituted heterocycle.

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a stillfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 5-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C4 alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet afurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 5-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 5-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, —OCH₃, —OCH₂CH₃, and—C(═O)NR^(3a)R^(3b). In a still further aspect, R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, —OCH₃, and—C(═O)NR^(3a)R^(3b).

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 5-membered heterocyclesubstituted with 0, 1, or 2 groups independently selected from halogen,C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a still furtheraspect, R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 5-membered heterocycle substitutedwith 0 or 1 group selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In yet a further aspect, R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5-membered heterocycle monosubstituted with a group selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 5-membered unsubstitutedheterocycle.

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 6-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a stillfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C4 alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet afurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, —OCH₃, —OCH₂CH₃, and—C(═O)NR^(3a)R^(3b). In a still further aspect, R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a6-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, —OCH₃, and—C(═O)NR^(3a)R^(3b).

In a further aspect, R¹ and R² are optionally covalently bonded and,together with the intermediate atoms, comprise a 6-membered heterocyclesubstituted with 0, 1, or 2 groups independently selected from halogen,C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a still furtheraspect, R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 6-membered heterocycle substitutedwith 0 or 1 group selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In yet a further aspect, R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a6-membered heterocycle monosubstituted with a group selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, R¹ and R² are optionally covalently bonded and, togetherwith the intermediate atoms, comprise a 6-membered unsubstitutedheterocycle.

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 5- to6-membered cycle substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered cycle substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, and—C(═O)NR^(3a)R^(3b). In yet a further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered cycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl, n-propyl,iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and—C(═O)NR^(3a)R^(3b). In an even further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered cycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl, —OCH₃,—OCH₂CH₃, and —C(═O)NR^(3a)R^(3b). In a still further aspect, eachoccurrence of R² is optionally covalently bonded and, together with theintermediate atoms, comprise a 5- to 6-membered cycle substituted with0, 1, 2, or 3 groups independently selected from fluorine, chlorine,methyl, —OCH₃, and —C(═O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 5- to6-membered cycle substituted with 0, 1, or 2 groups independentlyselected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered cycle substituted with 0 or 1 group selectedfrom halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In yeta further aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 5- to 6-memberedcycle monosubstituted with a group selected from halogen, C1-C8 alkyl,C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In an even further aspect, eachoccurrence of R² is optionally covalently bonded and, together with theintermediate atoms, comprise a 5- to 6-membered unsubstituted cycle.

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 5-memberedcycle substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a stillfurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 5-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C4 alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet afurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 5-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 5-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, —OCH₃, —OCH₂CH₃, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5-membered cycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, —OCH₃, and—C(═O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 5-memberedcycle substituted with 0, 1, or 2 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a stillfurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 5-membered cyclesubstituted with 0 or 1 group selected from halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b). In yet a further aspect, eachoccurrence of R² is optionally covalently bonded and, together with theintermediate atoms, comprise a 5-membered cycle monosubstituted with agroup selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In an even further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5-membered unsubstituted cycle.

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 6-memberedcycle substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a stillfurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 6-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C4 alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet afurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 6-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 6-membered cyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, —OCH₃, —OCH₂CH₃, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 6-membered cycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, —OCH₃, and—C(═O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 6-memberedcycle substituted with 0, 1, or 2 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In a stillfurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 6-membered cyclesubstituted with 0 or 1 group selected from halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(O)NR^(3a)R^(3b). In yet a further aspect, each occurrenceof R² is optionally covalently bonded and, together with theintermediate atoms, comprise a 6-membered cycle monosubstituted with agroup selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In an even further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 6-membered unsubstituted cycle.

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 5- to6-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered heterocycle substituted with 0, 1, 2, or 3groups independently selected from halogen, C1-C4 alkyl, C1-C4 alkoxy,and —C(═O)NR^(3a)R^(3b). In yet a further aspect, each occurrence of R²is optionally covalently bonded and, together with the intermediateatoms, comprise a 5- to 6-membered heterocycle substituted with 0, 1, 2,or 3 groups independently selected from fluorine, chlorine, methyl,ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,and —C(═O)NR^(3a)R^(3b). In an even further aspect, each occurrence ofR² is optionally covalently bonded and, together with the intermediateatoms, comprise a 5- to 6-membered heterocycle substituted with 0, 1, 2,or 3 groups independently selected from fluorine, chlorine, methyl,ethyl, —OCH₃, —OCH₂CH₃, and —C(═O)NR^(3a)R^(3b). In a still furtheraspect, each occurrence of R² is optionally covalently bonded and,together with the intermediate atoms, comprise a 5- to 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, methyl, —OCH₃, and —C(═O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 5- to6-membered heterocycle substituted with 0, 1, or 2 groups independentlyselected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered heterocycle substituted with 0 or 1 groupselected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In yet a further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered heterocycle monosubstituted with a groupselected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b). In an even further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5- to 6-membered unsubstituted heterocycle.

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 5-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In astill further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 5-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen, C1-C4 alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). In yeta further aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 5-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 5-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, methyl, ethyl, —OCH₃, —OCH₂CH₃, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 5-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, —OCH₃, and—C(═O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 5-memberedheterocycle substituted with 0, 1, or 2 groups independently selectedfrom halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In astill further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 5-memberedheterocycle substituted with 0 or 1 group selected from halogen, C1-C8alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet a further aspect,each occurrence of R² is optionally covalently bonded and, together withthe intermediate atoms, comprise a 5-membered heterocyclemonosubstituted with a group selected from halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(O)NR^(3a)R^(3b). In an even further aspect, eachoccurrence of R² is optionally covalently bonded and, together with theintermediate atoms, comprise a 5-membered unsubstituted heterocycle.

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In astill further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen, C1-C4 alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). In yeta further aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In an evenfurther aspect, each occurrence of R² is optionally covalently bondedand, together with the intermediate atoms, comprise a 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, methyl, ethyl, —OCH₃, —OCH₂CH₃, and—C(═O)NR^(3a)R^(3b). In a still further aspect, each occurrence of R² isoptionally covalently bonded and, together with the intermediate atoms,comprise a 6-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, —OCH₃, and—C(═O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 6-memberedheterocycle substituted with 0, 1, or 2 groups independently selectedfrom halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In astill further aspect, each occurrence of R² is optionally covalentlybonded and, together with the intermediate atoms, comprise a 6-memberedheterocycle substituted with 0 or 1 group selected from halogen, C1-C8alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In yet a further aspect,each occurrence of R² is optionally covalently bonded and, together withthe intermediate atoms, comprise a 6-membered heterocyclemonosubstituted with a group selected from halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(O)NR^(3a)R^(3b). In an even further aspect, eachoccurrence of R² is optionally covalently bonded and, together with theintermediate atoms, comprise a 6-membered unsubstituted heterocycle.

g. R^(3a) and R^(3b) Groups

In one aspect, each of R^(3a) and R^(3b) is independently selected fromhydrogen and C1-C4 alkyl. In a further aspect, each of R^(3a) and R^(3b)is independently selected from hydrogen, methyl, ethyl, n-propyl, andiso-propyl. In a still further aspect, each of R^(3a) and R^(3b) isindependently selected from hydrogen, methyl, and ethyl. In yet afurther aspect, each of R^(3a) and R^(3b) is independently selected fromhydrogen and ethyl. In an even further aspect, each of R^(3a) and R^(3b)is independently selected from hydrogen and methyl. In a still furtheraspect, each of R^(3a) and R^(3b) is hydrogen.

In a further aspect, each of R^(3a) and R^(3b) is independently selectedfrom C1-C4 alkyl. In a still further aspect, each of R^(3a) and R^(3b)is independently selected from methyl, ethyl, n-propyl, and iso-propyl.In yet a further aspect, each of R^(3a) and R^(3b) is independentlyselected from methyl and ethyl. In an even further aspect, each ofR^(3a) and R^(3b) is ethyl. In a still further aspect, each of R^(3a)and R^(3b) is methyl.

In a further aspect, R^(3a) is hydrogen and R^(3b) is C1-C4 alkyl. In astill further aspect, R^(3a) is hydrogen and R^(3b) is selected frommethyl, ethyl, n-propyl, and iso-propyl. In yet a further aspect, R^(3a)is hydrogen and R^(3b) is selected from methyl and ethyl. In an evenfurther aspect, R^(3a) is hydrogen and R^(3b) is ethyl. In a stillfurther aspect, R^(3a) is hydrogen and R^(3b) is methyl.

h. R⁴ Groups

In one aspect, R⁴ is selected from hydrogen and C1-C8 alkyl. In afurther aspect, R⁴ is selected from hydrogen and C1-C4 alkyl. In a stillfurther aspect, R⁴ is selected from hydrogen, methyl, ethyl, n-propyl,and iso-propyl. In yet a further aspect, R⁴ is hydrogen.

In a further aspect, R⁴ is C1-C8 alkyl. In a still further aspect, R⁴ isselected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, and tert-butyl. In yet a further aspect, R⁴ is selected frommethyl, ethyl, n-propyl, and iso-propyl. In an even further aspect, R⁴is selected from methyl and ethyl. In a still further aspect, R⁴ isethyl. In yet a further aspect, R⁴ is methyl.

i. R⁵ Groups

In one aspect, R⁵ is C1-C8 alkyl. In a further aspect, R⁵ is selectedfrom methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,and tert-butyl. In a still further aspect, R⁵ is selected from methyl,ethyl, n-propyl, and iso-propyl. In yet a further aspect, R⁵ is selectedfrom methyl and ethyl. In an even further aspect, R⁵ is ethyl. In astill further aspect, R⁵ is methyl.

j. R⁶ and R⁷ Groups

In one aspect, each of R⁶ and R⁷ is independently selected from C1-C8alkyl. In a further aspect, each of R⁶ and R⁷ is independently selectedfrom methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,and tert-butyl. In a still further aspect, each of R⁶ and R⁷ isindependently selected from methyl, ethyl, n-propyl, and iso-propyl. Inyet a further aspect, each of R⁶ and R⁷ is independently selected frommethyl and ethyl. In an even further aspect, each of R⁶ and R⁷ is ethyl.In a still further aspect, each of R⁶ and R⁷ is methyl.

k. R^(11a) and R^(11b) Groups

In one aspect, each of R^(11a) and R^(11b) is independently selectedfrom hydrogen and C1-C4 alkyl. In a further aspect, each of R^(11a) andR^(11b) is independently selected from hydrogen, methyl, ethyl,n-propyl, and iso-propyl. In a still further aspect, each of R^(11a) andR^(11b) is independently selected from hydrogen, methyl, and ethyl. Inyet a further aspect, each of R^(11a) and R^(11b) is independentlyselected from hydrogen and ethyl. In an even further aspect, each ofR^(11a) and R^(11b) is independently selected from hydrogen and methyl.In a still further aspect, each of R^(11a) and R^(11b) is hydrogen.

In a further aspect, each of R^(11a) and R^(11b) is independentlyselected from C1-C4 alkyl. In a still further aspect, each of R^(11a)and R^(11b) is independently selected from methyl, ethyl, n-propyl, andiso-propyl. In yet a further aspect, each of R^(11a) and R^(11b) isindependently selected from methyl and ethyl. In an even further aspect,each of R^(11a) and R^(11b) is ethyl. In a still further aspect, each ofR^(11a) and R^(11b) is methyl.

In a further aspect, R^(11a) is hydrogen and R^(11b) is C1-C4 alkyl. Ina still further aspect, R^(11a) is hydrogen and R^(11b) is selected frommethyl, ethyl, n-propyl, and iso-propyl. In yet a further aspect,R^(11a) is hydrogen and R^(11b) is selected from methyl and ethyl. In aneven further aspect, R^(11a) is hydrogen and R^(11b) is ethyl. In astill further aspect, R^(11a) is hydrogen and R^(11b) is methyl.

l. R^(12a), R^(12b), and R¹³ Groups

In one aspect, each of R^(12a), R^(12b), and R¹³, when present, isindependently selected from hydrogen and C1-C4 alkyl. In a furtheraspect, each of R^(12a), R^(12b), and R¹³, when present, isindependently selected from hydrogen, methyl, ethyl, n-propyl, andiso-propyl. In a still further aspect, each of R^(12a), R^(12b), andR¹³, when present, is independently selected from hydrogen, methyl, andethyl. In yet a further aspect, each of R^(12a), R^(12b), and R¹³, whenpresent, is independently selected from hydrogen and ethyl. In an evenfurther aspect, each of R^(12a), R^(12b), and R¹³, when present, isindependently selected from hydrogen and methyl. In a still furtheraspect, each of R^(12a), R^(12b), and R¹³, when present, is hydrogen.

In a further aspect, each of R^(12a), R^(12b), and R¹³, when present, isindependently selected from C1-C4 alkyl. In a still further aspect, eachof R^(12a), R^(12b), and R¹³, when present, is independently selectedfrom methyl, ethyl, n-propyl, and iso-propyl. In yet a further aspect,each of R^(12a), R^(12b), and R¹³, when present, is independentlyselected from methyl and ethyl. In an even further aspect, each ofR^(12a), R^(12b), and R¹³, when present, is ethyl. In a still furtheraspect, each of R^(12a), R^(12b), and R¹³, when present, is methyl.

In a further aspect, R^(12a), when present, is hydrogen and R^(12b),when present, is C1-C4 alkyl. In a still further aspect, R^(12a), whenpresent, is hydrogen and R^(12b), when present, is selected from methyl,ethyl, n-propyl, and iso-propyl. In yet a further aspect, R^(12a), whenpresent, is hydrogen and R^(12b), when present, is selected from methyland ethyl. In an even further aspect, R^(12a), when present, is hydrogenand R^(12b), when present, is ethyl. In a still further aspect, R^(12a),when present, is hydrogen and R^(12b), when present, is methyl.

m. R¹⁴ Groups

In one aspect, each occurrence of R⁴ is independently selected fromhydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(O)NR^(3a)R^(3b). Ina further aspect, each occurrence of R¹⁴ is independently selected fromhydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b).In a still further aspect, each occurrence of R¹⁴ is independentlyselected from hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl,iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, and—C(═O)NR^(3a)R^(3b). In yet a further aspect, each occurrence of R¹⁴ isindependently selected from hydrogen, fluorine, chlorine, methyl, ethyl,—OCH₃, —OCH₂CH₃, and —C(═O)NR^(3a)R^(3b). In an even further aspect,each occurrence of R¹⁴ is independently selected from hydrogen,fluorine, chlorine, methyl, —OCH₃, and —C(═O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R⁴ is independently selectedfrom hydrogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b). In astill further aspect, each occurrence of R¹⁴ is independently selectedfrom hydrogen, C1-C4 alkyl, C1-C4 alkoxy, and —C(═O)NR^(3a)R^(3b). Inyet a further aspect, each occurrence of R¹⁴ is independently selectedfrom hydrogen, methyl, ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃,—OCH₂CH₂CH₃, —OCH(CH₃)₂, and —C(═O)NR^(3a)R^(3b). In an even furtheraspect, each occurrence of R¹⁴ is independently selected from hydrogen,methyl, ethyl, —OCH₃, —OCH₂CH₃, and —C(═O)NR^(3a)R^(3b). In a stillfurther aspect, each occurrence of R¹⁴ is independently selected fromhydrogen, methyl, —OCH₃, and —C(═O)NR^(3a)R^(3b).

In a further aspect, each occurrence of R⁴ is independently selectedfrom hydrogen, C1-C8 alkyl, and C1-C8 alkoxy. In a still further aspect,each occurrence of R¹⁴ is independently selected from hydrogen, C1-C4alkyl, and C1-C4 alkoxy. In yet a further aspect, each occurrence of R¹⁴is independently selected from hydrogen, methyl, ethyl, n-propyl,iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, and —OCH(CH₃)₂. In an evenfurther aspect, each occurrence of R¹⁴ is independently selected fromhydrogen, methyl, ethyl, —OCH₃, and —OCH₂CH₃. In a still further aspect,each occurrence of R¹⁴ is independently selected from hydrogen, methyl,and —OCH₃.

In a further aspect, each occurrence of R⁴ is independently selectedfrom hydrogen and halogen. In a still further aspect, each occurrence ofR¹⁴ is independently selected from hydrogen, fluorine, and chlorine. Inyet a further aspect, each occurrence of R¹⁴ is independently selectedfrom hydrogen and chlorine. In a still further aspect, each occurrenceof R¹⁴ is independently selected from hydrogen and fluorine. In yet afurther aspect, each occurrence of R¹⁴ is hydrogen.

n. Ar¹ Groups

In one aspect, Ar¹ is a 3- to 6-membered heterocycle substituted with 0,1, 2, or 3 groups independently selected from halogen and C1-C8 alkyl.In a further aspect, Ar¹ is a 3- to 6-membered heterocycle substitutedwith 0, 1, 2, or 3 groups independently selected from halogen and C1-C4alkyl.

In a further aspect, Ar¹ is a 3- to 6-membered heterocycle substitutedwith 0, 1, or 2 groups independently selected from halogen and C1-C8alkyl. In a still further aspect, Ar¹ is a 3- to 6-membered heterocyclesubstituted with 0 or 1 group selected from halogen and C1-C8 alkyl. Inyet a further aspect, Ar¹ is a 3- to 6-membered heterocyclemonosubstituted with a group selected from halogen and C1-C8 alkyl. Inan even further aspect, Ar¹ is a 3- to 6-membered unsubstitutedheterocycle.

In a further aspect, Ar¹ is a 3- to 6-membered heterocycle substitutedwith 0, 1, 2, or 3 groups independently selected from fluorine,chlorine, and C1-C8 alkyl. In a still further aspect, Ar¹ is a 3- to6-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, n-propyl, iso-butyl, sec-butyl, n-butyl, and tert-butyl. Inyet a further aspect, Ar¹ is a 3- to 6-membered heterocycle substitutedwith 0, 1, 2, or 3 groups independently selected from fluorine,chlorine, methyl, ethyl, iso-propyl, and n-propyl. In an even furtheraspect, Ar¹ is a 3- to 6-membered heterocycle substituted with 0, 1, 2,or 3 groups independently selected from fluorine, chlorine, methyl, andethyl. In a still further aspect, Ar¹ is a 3- to 6-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, and methyl.

In a further aspect, Ar¹ is a 3- to 6-membered nitrogen-containingheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen and C1-C8 alkyl. In a still further aspect, Ar¹ is a 3- to6-membered nitrogen-containing heterocycle substituted with 0, 1, or 2groups independently selected from halogen and C1-C8 alkyl. In yet afurther aspect, Ar¹ is a 3- to 6-membered nitrogen-containingheterocycle substituted with 0 or 1 group selected from halogen andC1-C8 alkyl. In an even further aspect, Ar¹ is a 3- to 6-memberednitrogen-containing heterocycle monosubstituted with a group selectedfrom halogen and C1-C8 alkyl. In a still further aspect, Ar¹ is a 3- to6-membered unsubstituted nitrogen-containing heterocycle.

In a further aspect, Ar¹ is a 3- to 6-membered nitrogen-containingheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, and C1-C8 alkyl. In a still further aspect, Ar¹is a 3- to 6-membered nitrogen-containing heterocycle substituted with0, 1, 2, or 3 groups independently selected from fluorine, chlorine,methyl, ethyl, iso-propyl, n-propyl, iso-butyl, sec-butyl, n-butyl, andtert-butyl. In yet a further aspect, Ar¹ is a 3- to 6-memberednitrogen-containing heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, Ar¹ is a 3- to6-membered nitrogen-containing heterocycle substituted with 0, 1, 2, or3 groups independently selected from fluorine, chlorine, methyl, andethyl. In a still further aspect, Ar¹ is a 3- to 6-memberednitrogen-containing heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, and methyl.

In a further aspect, Ar¹ is a 3-membered heterocycle substituted with 0,1, 2, or 3 groups independently selected from halogen and C1-C8 alkyl.In a still further aspect, Ar¹ is a 3-membered heterocycle substitutedwith 0, 1, or 2 groups independently selected from halogen and C1-C8alkyl. In yet a further aspect, Ar¹ is a 3-membered heterocyclesubstituted with 0 or 1 group selected from halogen and C1-C8 alkyl. Inan even further aspect, Ar¹ is a 3-membered heterocycle monosubstitutedwith a group selected from halogen and C1-C8 alkyl. In a still furtheraspect, Ar¹ is a 3-membered unsubstituted heterocycle.

In a further aspect, Ar¹ is a 3-membered heterocycle substituted with 0,1, 2, or 3 groups independently selected from fluorine, chlorine, andC1-C8 alkyl. In a still further aspect, Ar¹ is a 3-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, iso-propyl, n-propyl, iso-butyl,sec-butyl, n-butyl, and tert-butyl. In yet a further aspect, Ar¹ is a3-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, Ar¹ is a 3-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, methyl, and ethyl. In a still further aspect,Ar¹ is a 3-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, and methyl.

In a further aspect, Ar¹ is a 4-membered heterocycle substituted with 0,1, 2, or 3 groups independently selected from halogen and C1-C8 alkyl.In a still further aspect, Ar¹ is a 4-membered heterocycle substitutedwith 0, 1, or 2 groups independently selected from halogen and C1-C8alkyl. In yet a further aspect, Ar¹ is a 4-membered heterocyclesubstituted with 0 or 1 group selected from halogen and C1-C8 alkyl. Inan even further aspect, Ar¹ is a 4-membered heterocycle monosubstitutedwith a group selected from halogen and C1-C8 alkyl. In a still furtheraspect, Ar¹ is a 4-membered unsubstituted heterocycle.

In a further aspect, Ar¹ is a 4-membered heterocycle substituted with 0,1, 2, or 3 groups independently selected from fluorine, chlorine, andC1-C8 alkyl. In a still further aspect, Ar¹ is a 4-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, iso-propyl, n-propyl, iso-butyl,sec-butyl, n-butyl, and tert-butyl. In yet a further aspect, Ar¹ is a4-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, Ar¹ is a 4-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, methyl, and ethyl. In a still further aspect,Ar¹ is a 4-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, and methyl.

In a further aspect, Ar¹ is a 5-membered heterocycle substituted with 0,1, 2, or 3 groups independently selected from halogen and C1-C8 alkyl.In a still further aspect, Ar¹ is a 5-membered heterocycle substitutedwith 0, 1, or 2 groups independently selected from halogen and C1-C8alkyl. In yet a further aspect, Ar¹ is a 5-membered heterocyclesubstituted with 0 or 1 group selected from halogen and C1-C8 alkyl. Inan even further aspect, Ar¹ is a 5-membered heterocycle monosubstitutedwith a group selected from halogen and C1-C8 alkyl. In a still furtheraspect, Ar¹ is a 5-membered unsubstituted heterocycle.

In a further aspect, Ar¹ is a 5-membered heterocycle substituted with 0,1, 2, or 3 groups independently selected from fluorine, chlorine, andC1-C8 alkyl. In a still further aspect, Ar¹ is a 5-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, iso-propyl, n-propyl, iso-butyl,sec-butyl, n-butyl, and tert-butyl. In yet a further aspect, Ar¹ is a5-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, Ar¹ is a 5-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, methyl, and ethyl. In a still further aspect,Ar¹ is a 5-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, and methyl.

In a further aspect, Ar¹ is a 6-membered heterocycle substituted with 0,1, 2, or 3 groups independently selected from halogen and C1-C8 alkyl.In a still further aspect, Ar¹ is a 6-membered heterocycle substitutedwith 0, 1, or 2 groups independently selected from halogen and C1-C8alkyl. In yet a further aspect, Ar¹ is a 6-membered heterocyclesubstituted with 0 or 1 group selected from halogen and C1-C8 alkyl. Inan even further aspect, Ar¹ is a 6-membered heterocycle monosubstitutedwith a group selected from halogen and C1-C8 alkyl. In a still furtheraspect, Ar¹ is a 6-membered unsubstituted heterocycle.

In a further aspect, Ar¹ is a 6-membered heterocycle substituted with 0,1, 2, or 3 groups independently selected from fluorine, chlorine, andC1-C8 alkyl. In a still further aspect, Ar¹ is a 6-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, iso-propyl, n-propyl, iso-butyl,sec-butyl, n-butyl, and tert-butyl. In yet a further aspect, Ar¹ is a6-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, Ar¹ is a 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, methyl, and ethyl. In a still further aspect,Ar¹ is a 6-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, and methyl.

In a further aspect, Ar¹ is pyrazole substituted with 0, 1, 2, or 3groups independently selected from halogen and C1-C8 alkyl. In a stillfurther aspect, Ar¹ is a 3- to 6-membered nitrogen-containingheterocycle substituted with 0, 1, or 2 groups independently selectedfrom halogen and C1-C8 alkyl. In yet a further aspect, Ar¹ is pyrazolesubstituted with 0 or 1 group selected from halogen and C1-C8 alkyl. Inan even further aspect, Ar¹ is pyrazole monosubstituted with a groupselected from halogen and C1-C8 alkyl. In a still further aspect, Ar¹ isunsubstituted pyrazole.

In a further aspect, Ar¹ is pyrazole substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, and C1-C8 alkyl.In a still further aspect, Ar¹ is pyrazole substituted with 0, 1, 2, or3 groups independently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, n-propyl, iso-butyl, sec-butyl, n-butyl, and tert-butyl. Inyet a further aspect, Ar¹ is pyrazole substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, Ar¹ is pyrazolesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, and ethyl. In a still further aspect, Ar¹ ispyrazole substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, and methyl.

In a further aspect, Ar¹ is triazole substituted with 0, 1, 2, or 3groups independently selected from halogen and C1-C8 alkyl. In a stillfurther aspect, Ar¹ is a 3- to 6-membered nitrogen-containingheterocycle substituted with 0, 1, or 2 groups independently selectedfrom halogen and C1-C8 alkyl. In yet a further aspect, Ar¹ is triazolesubstituted with 0 or 1 group selected from halogen and C1-C8 alkyl. Inan even further aspect, Ar¹ is triazole monosubstituted with a groupselected from halogen and C1-C8 alkyl. In a still further aspect, Ar¹ isunsubstituted triazole.

In a further aspect, Ar¹ is triazole substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, and C1-C8 alkyl.In a still further aspect, Ar¹ is triazole substituted with 0, 1, 2, or3 groups independently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, n-propyl, iso-butyl, sec-butyl, n-butyl, and tert-butyl. Inyet a further aspect, Ar¹ is triazole substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, Ar¹ is triazolesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, and ethyl. In a still further aspect, Ar¹ istriazole substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, and methyl.

o. Ar² Groups

In one aspect, Ar² is selected from aryl and heteroaryl and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen and C1-C8alkyl. In a further aspect, Ar² is selected from aryl and heteroaryl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen and C1-C4 alkyl.

In a further aspect, Ar² is selected from aryl and heteroaryl andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —NH₂, C1-C8 alkyl, C1-C8 alkylamino, (C1-C8)(C1-C8)dialkylamino, C1-C8 aminoalkyl, and —N(CO₂(C1-C8 alkyl))₂. In a stillfurther aspect, Ar² is selected from aryl and heteroaryl and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —NH₂,C1-C4 alkyl, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino, C1-C4aminoalkyl, and —N(CO₂(C1-C4 alkyl))₂.

In a further aspect, Ar² is selected from aryl and heteroaryl andsubstituted with 0, 1, 2, or 3 groups independently selected from —NH₂,C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, C1-C8 aminoalkyl, and—N(CO₂(C1-C8 alkyl))₂. In a still further aspect, Ar² is selected fromaryl and heteroaryl and substituted with 0, 1, 2, or 3 groupsindependently selected from —NH₂, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C1-C4 aminoalkyl, and —N(CO₂(C1-C4 alkyl))₂. In yet afurther aspect, Ar² is selected from aryl and heteroaryl and substitutedwith 0, 1, 2, or 3 groups independently selected from —NH₂, —NHCH₃,—NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)(CH₂CH₃),—N(CH₃)(CH₂CH₂CH₃), —N(CH₃)(CH(CH₃)₂), —N(CH₂CH₃)₂,—N(CH₂CH₃)(CH₂CH₂CH₃), —N(CH₂CH₃)(CH(CH₃)₂), —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₃)(CH(CH₃)₂), —N(CH(CH₃)₂)₂, —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH(CO₂CH₃)NHCO₂C(CH₃)₃, —N(CO₂CH₃)₂, —N(CO₂CH₂CH₃)₂,—N(CO₂CH₂CH₂CH₃)₂, —N(CO₂CH(CH₃)₂)₂, and —N(CO₂C(CH₃)₃)₂.

In a further aspect, Ar² is selected from aryl and heteroaryl andsubstituted with 0, 1, or 2 groups independently selected from halogenand C1-C8 alkyl. In a still further aspect, Ar² is selected from aryland heteroaryl and substituted with 0 or 1 group selected from halogenand C1-C8 alkyl. In yet a further aspect, Ar² is selected from aryl andheteroaryl and monosubstituted with a group selected from halogen andC1-C8 alkyl. In an even further aspect, Ar² is selected from aryl andheteroaryl and is unsubstituted.

In a further aspect, Ar² is selected from aryl and heteroaryl andsubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, and C1-C8 alkyl. In a still further aspect, Ar² isselected from aryl and heteroaryl and substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, n-propyl, iso-butyl, sec-butyl, n-butyl, and tert-butyl. Inyet a further aspect, Ar² is selected from aryl and heteroaryl andsubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, iso-propyl, and n-propyl. In an evenfurther aspect, Ar² is selected from aryl and heteroaryl and substitutedwith 0, 1, 2, or 3 groups independently selected from fluorine,chlorine, methyl, and ethyl. In a still further aspect, Ar² is selectedfrom aryl and heteroaryl and substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, and methyl.

In a further aspect, Ar² is aryl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen and C1-C8 alkyl. In a still furtheraspect, Ar² is aryl substituted with 0, 1, or 2 groups independentlyselected from halogen and C1-C8 alkyl. In yet a further aspect, Ar² isaryl substituted with 0 or 1 group selected from halogen and C1-C8alkyl. In an even further aspect, Ar² is aryl monosubstituted with agroup selected from halogen and C1-C8 alkyl. In a still further aspect,Ar² is unsubstituted aryl.

In a further aspect, Ar² is aryl substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, and C1-C8 alkyl. In astill further aspect, Ar² is aryl substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, n-propyl, iso-butyl, sec-butyl, n-butyl, and tert-butyl. Inyet a further aspect, Ar² is aryl substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, Ar² is arylsubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, and ethyl. In a still further aspect, Ar² isaryl substituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, and methyl.

In a further aspect, Ar² is phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen and C1-C8 alkyl. In a still furtheraspect, Ar² is phenyl substituted with 0, 1, or 2 groups independentlyselected from halogen and C1-C8 alkyl. In yet a further aspect, Ar² isphenyl substituted with 0 or 1 group selected from halogen and C1-C8alkyl. In an even further aspect, Ar² is phenyl monosubstituted with agroup selected from halogen and C1-C8 alkyl. In a still further aspect,Ar² is unsubstituted phenyl.

In a further aspect, Ar² is phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, and C1-C8 alkyl. In astill further aspect, Ar² is phenyl substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, n-propyl, iso-butyl, sec-butyl, n-butyl, and tert-butyl. Inyet a further aspect, Ar² is phenyl substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, Ar² is phenylsubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, and ethyl. In a still further aspect, Ar² isphenyl substituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, and methyl.

In a further aspect, Ar² is heteroaryl substituted with 0, 1, 2, or 3groups independently selected from halogen and C1-C8 alkyl. In a stillfurther aspect, Ar² is heteroaryl substituted with 0, 1, or 2 groupsindependently selected from halogen and C1-C8 alkyl. In yet a furtheraspect, Ar² is heteroaryl substituted with 0 or 1 group selected fromhalogen and C1-C8 alkyl. In an even further aspect, Ar² is heteroarylmonosubstituted with a group selected from halogen and C1-C8 alkyl. In astill further aspect, Ar² is unsubstituted heteroaryl.

In a further aspect, Ar² is heteroaryl substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, and C1-C8 alkyl.In a still further aspect, Ar² is heteroaryl substituted with 0, 1, 2,or 3 groups independently selected from fluorine, chlorine, methyl,ethyl, iso-propyl, n-propyl, iso-butyl, sec-butyl, n-butyl, andtert-butyl. In yet a further aspect, Ar² is heteroaryl substituted with0, 1, 2, or 3 groups independently selected from fluorine, chlorine,methyl, ethyl, iso-propyl, and n-propyl. In an even further aspect, Ar²is heteroaryl substituted with 0, 1, 2, or 3 groups independentlyselected from fluorine, chlorine, methyl, and ethyl. In a still furtheraspect, Ar² is heteroaryl substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, and methyl.

In a further aspect, Ar² is pyridinyl substituted with 0, 1, 2, or 3groups independently selected from halogen and C1-C8 alkyl. In a stillfurther aspect, Ar² is pyridinyl substituted with 0, 1, or 2 groupsindependently selected from halogen and C1-C8 alkyl. In yet a furtheraspect, Ar² is pyridinyl substituted with 0 or 1 group selected fromhalogen and C1-C8 alkyl. In an even further aspect, Ar² is pyridinylmonosubstituted with a group selected from halogen and C1-C8 alkyl. In astill further aspect, Ar² is unsubstituted pyridinyl.

In a further aspect, Ar² is pyridinyl substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, and C1-C8 alkyl.In a still further aspect, Ar² is pyridinyl substituted with 0, 1, 2, or3 groups independently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, n-propyl, iso-butyl, sec-butyl, n-butyl, and tert-butyl. Inyet a further aspect, Ar² is pyridinyl substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, and n-propyl. In an even further aspect, Ar² is pyridinylsubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, and ethyl. In a still further aspect, Ar² ispyridinyl substituted with 0, 1, 2, or 3 groups independently selectedfrom fluorine, chlorine, and methyl.

In a further aspect, Ar² is a purine substituted with 0, 1, 2, or 3groups independently selected from halogen, —NH₂, C1-C8 alkyl, C1-C8alkylamino, (C1-C8)(C1-C8) dialkylamino, C1-C8 aminoalkyl, and—N(CO₂(C1-C8 alkyl))₂. In a still further aspect, Ar² is a purinesubstituted with 0, 1, or 2 groups independently selected from halogen,—NH₂, C1-C8 alkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, C1-C8aminoalkyl, and —N(CO₂(C1-C8 alkyl))₂. In yet a further aspect, Ar² is apurine substituted with 0 or 1 group selected from halogen, —NH₂, C1-C8alkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, C1-C8 aminoalkyl,and —N(CO₂(C1-C8 alkyl))₂. In an even further aspect, Ar² is a purinemonosubstituted with a group selected from halogen, —NH₂, C1-C8 alkyl,C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, C1-C8 aminoalkyl, and—N(CO₂(C1-C8 alkyl))₂. In a still further aspect, Ar² is anunsubstituted purine.

In a further aspect, Ar² is a purine substituted with 0, 1, 2, or 3groups independently selected from fluorine, chlorine, —NH₂, C1-C8alkyl, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, C1-C8 aminoalkyl,and —N(CO₂(C1-C8 alkyl))₂. In a still further aspect, Ar² is a purinesubstituted with 0, 1, 2, or 3 groups independently selected fromfluorine, chlorine, methyl, ethyl, iso-propyl, n-propyl, iso-butyl,sec-butyl, n-butyl, tert-butyl, —NH₂, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino, C1-C4 aminoalkyl, and —N(CO₂(C1-C4 alkyl))₂. In yet afurther aspect, Ar² is a purine substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl,iso-propyl, n-propyl, —NH₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)(CH₂CH₃), —N(CH₃)(CH₂CH₂CH₃),—N(CH₃)(CH(CH₃)₂), —N(CH₂CH₃)₂, —N(CH₂CH₃)(CH₂CH₂CH₃),—N(CH₂CH₃)(CH(CH₃)₂), —N(CH₂CH₂CH₃)₂, —N(CH₂CH₂CH₃)(CH(CH₃)₂),—N(CH(CH₃)₂)₂, —CH₂NH₂, —CH₂CH₂NH₂, —CH₂CH(CO₂CH₃)NHCO₂C(CH₃)₃,—N(CO₂CH₃)₂, —N(CO₂CH₂CH₃)₂, —N(CO₂CH₂CH₂CH₃)₂, —N(CO₂CH(CH₃)₂)₂, and—N(CO₂C(CH₃)₃)₂. In an even further aspect, Ar² is a purine substitutedwith 0, 1, 2, or 3 groups independently selected from fluorine,chlorine, methyl, ethyl, —NH₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂,—N(CH₃)(CH₂CH₃), —N(CH₂CH₃)₂, —CH₂NH₂, —CH₂CH₂NH₂,—CH₂CH(CO₂CH₃)NHCO₂C(CH₃)₃, —N(CO₂CH₃)₂, —N(CO₂CH₂CH₃)₂, and—N(CO₂C(CH₃)₃)₂. In a still further aspect, Ar² is a purine substitutedwith 0, 1, 2, or 3 groups independently selected from fluorine,chlorine, methyl, —NH₂, —NHCH₃, —N(CH₃)₂, —CH₂NH₂,—CH₂CH(CO₂CH₃)NHCO₂C(CH₃)₃, and —N(CO₂C(CH₃)₃)₂.

2. Example Structures

In one aspect, a compound can be present as:

E. Acridnium Photocatalysts

In one aspect, acridinium photocatalysts are disclosed. It iscontemplated that each disclosed derivative can be optionally furthersubstituted. It is also contemplated that any one or more derivative canbe optionally omitted from the invention. It is understood that adisclosed compound can be provided by the disclosed methods.

1. Structure

In one aspect, disclosed are acridinium photocatalysts having astructure represented by a formula:

wherein X is selected from BF₄, TfO, PF₆, and ClO₄; wherein each ofR^(8a), R^(8b), R^(8c), R^(8d), R^(8a′), R^(8b′), R^(8c′), and R^(8d′)is independently selected from hydrogen, halogen, —CF₃, —NH₂, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 dialkylamino, and phenylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino; wherein R⁹ is selected from C1-C4 alkyl andphenyl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino; and wherein R¹⁰ is selected from C1-C4alkyl and phenyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen and C1-C4 alkyl.

In a further aspect, the acridinium photocatalyst has a structureselected from:

In a further aspect, the acridinium photocatalyst has a structure:

a. X Groups

In one aspect, X is selected from BF₄, TfO, PF₆, and ClO₄. In a furtheraspect, X is selected from BF₄, TfO, and PF₆. In a still further aspect,X is selected from BF₄ and PF₆. In yet a further aspect, X is ClO₄. Inan even further aspect, X is TfO. In a still further aspect, X is BF₄.In yet a further aspect, X is PF₆.

b. R^(8a), R^(8b), R^(8c), R^(8d), R^(8a′), R^(8b′), R^(8c′), andR^(8d′) Groups

In one aspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R^(8a′), R^(8b′),R^(8c′), and R^(8d′) is independently selected from hydrogen, halogen,—CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4dialkylamino, and phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino.

In a further aspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R^(8a′),R^(8b′), R^(8c′), and R^(8d′) is independently selected from hydrogen,halogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4dialkylamino. In a still further aspect, each of R^(8a), R^(8b), R^(8c),R^(8d), R^(8a′), R^(8b′), R^(8c′), and R^(8d′) is independently selectedfrom hydrogen, halogen, —CF₃, —NH₂, methyl, ethyl, n-propyl, iso-propyl,—OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, —NHCH₃, —NHCH₂CH₃,—NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)(CH₂CH₃),—N(CH₃)(CH₂CH₂CH₃), —N(CH₃)(CH(CH₃)₂), —N(CH₂CH₃)₂,—N(CH₂CH₃)(CH₂CH₂CH₃), —N(CH₂CH₃)(CH(CH₃)₂), —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₃)(CH(CH₃)₂), and —N(CH(CH₃)₂)₂. In yet a further aspect,each of R^(8a), R^(8b), R^(8c), R^(8d), R^(8a′), R^(8b′), R^(8′), andR^(8d′) is independently selected from hydrogen, halogen, —CF₃, —NH₂,methyl, ethyl, —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂, —NHCH₃, —N(CH₃)₂,—N(CH₃)(CH₂CH₃), and —N(CH₂CH₃)₂. In an even further aspect, each ofR^(8a), R^(8b), R^(8c), R^(8d), R^(8a′), R^(8b′), R^(8c′), and R^(8d′)is independently selected from hydrogen, halogen, —CF₃, —NH₂, methyl,—OCH₃, —OCH(CH₃)₂, —NHCH₃, and —N(CH₃)₂.

In a further aspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R^(8a′),R^(8b′), R^(8d′), and R^(8d′) is independently selected from hydrogen,C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 dialkylamino. In astill further aspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R^(8a′),R^(8b′), R^(8c′), and R^(8d′) is independently selected from hydrogen,methyl, ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃,—OCH(CH₃)₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂,—N(CH₃)(CH₂CH₃), —N(CH₃)(CH₂CH₂CH₃), —N(CH₃)(CH(CH₃)₂), —N(CH₂CH₃)₂,—N(CH₂CH₃)(CH₂CH₂CH₃), —N(CH₂CH₃)(CH(CH₃)₂), —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₃)(CH(CH₃)₂), and —N(CH(CH₃)₂)₂. In yet a further aspect,each of R^(8a), R^(8b), R^(8c), R^(8d), R_(8a′), R^(8b′), R^(8c′), andR^(8d′) is independently selected from hydrogen, methyl, ethyl, —OCH₃,—OCH₂CH₃, —OCH(CH₃)₂, —NHCH₃, —N(CH₃)₂, —N(CH₃)(CH₂CH₃), and—N(CH₂CH₃)₂. In an even further aspect, each R^(8a), R^(8b), R^(8c),R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′) is independently selectedfrom hydrogen, methyl, —OCH₃, —OCH(CH₃)₂, —NHCH₃, and —N(CH₃)₂.

In a further aspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R_(8a′),R^(8b′), R^(8c′), and R^(8d′) is independently selected from hydrogenand C1-C4 alkyl. In a still further aspect, each of R^(8a), R^(8b),R^(8c), R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′) is independentlyselected from hydrogen, methyl, ethyl, n-propyl, and iso-propyl. In yeta further aspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R_(8a′),R^(8b′), R^(8c′), and R^(8d′) is independently selected from hydrogen,methyl, and ethyl. In an even further aspect, each of R^(8a), R^(8b),R^(8c), R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′) is independentlyselected from hydrogen and methyl.

In a further aspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R_(8a′),R^(8b′), R^(8c′), and R^(8d′) is independently selected from hydrogenand halogen. In a still further aspect, each of R^(8a), R^(8b), R^(8c),R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′) is independently selectedfrom hydrogen, fluorine, and chlorine. In yet a further aspect, each ofR^(8a), R^(8b), R^(8c), R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′)is independently selected from hydrogen and fluorine. In an even furtheraspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R_(8a′), R^(8b′),R^(8c′), and R^(8d′) is independently selected from hydrogen andchlorine.

In a further aspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R_(8a′),R^(8b′), R^(8c′), and R^(8d′) is independently selected from hydrogenand phenyl substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino. In a still further aspect, each of R^(8a),R^(8b), R^(8c), R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′) isindependently selected from hydrogen and phenyl substituted with 0, 1,or 2 groups independently selected from halogen, —CF₃, —NH₂, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. Inyet a further aspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R_(8a′),R^(8b′), R^(8c′), and R^(8d′) is independently selected from hydrogenand phenyl substituted with 0 or 1 group selected from halogen, —CF₃,—NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino. In an even further aspect, each of R^(8a), R^(8b), R^(8c),R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′) is independently selectedfrom hydrogen and phenyl monosubstituted with a group selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino. In a still further aspect, each of R^(8a),R^(8b), R^(8c), R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′) isindependently selected from hydrogen and unsubstituted phenyl.

In a further aspect, each of R^(8a), R^(8b), R^(8c), R^(8d), R_(8a′),R^(8b′), R^(8c′), and R^(8d′) is independently selected from hydrogenand phenyl substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen, —CF₃, —NH₂, methyl, ethyl, n-propyl, iso-propyl, —OCH₃,—OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂, —NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)(CH₂CH₃), —N(CH₃)(CH₂CH₂CH₃),—N(CH₃)(CH(CH₃)₂), —N(CH₂CH₃)₂, —N(CH₂CH₃)(CH₂CH₂CH₃),—N(CH₂CH₃)(CH(CH₃)₂), —N(CH₂CH₂CH₃)₂, —N(CH₂CH₂CH₃)(CH(CH₃)₂), and—N(CH(CH₃)₂)₂. In a still further aspect, each of R^(8a), R^(8b),R^(8c), R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′) is independentlyselected from hydrogen and phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, —CF₃, —NH₂, methyl,ethyl, —OCH₃, —OCH₂CH₃, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₃)(CH₂CH₃),and —N(CH₂CH₃)₂. In yet a further aspect, each of R^(8a), R^(8b),R^(8c), R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′) is independentlyselected from hydrogen and phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, —CF₃, —NH₂, methyl,—OCH₃, —NHCH₃, and —N(CH₃)₂.

c. R⁹ Groups

In one aspect, R⁹ is selected from C1-C4 alkyl and phenyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen, —CF₃,—NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4)dialkylamino.

In a further aspect, R⁹ is C1-C4 alkyl. In a still further aspect, R⁹ isselected from methyl, ethyl, n-propyl, and iso-propyl. In yet a furtheraspect, R⁹ is selected from methyl and ethyl. In an even further aspect,R⁹ is ethyl. In a still further aspect, R⁹ is methyl.

In a further aspect, R⁹ is phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. In a stillfurther aspect, R⁹ is phenyl substituted with 0, 1, or 2 groupsindependently selected from halogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. In yet a furtheraspect, R⁹ is phenyl substituted with 0 or 1 group selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino. In an even further aspect, R⁹ is phenylmonosubstituted with a group selected from halogen, —CF₃, —NH₂, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, (C1-C4)(C1-C4) dialkylamino. In astill further aspect, R⁹ is unsubstituted phenyl.

In a further aspect, R⁹ is phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, —CF₃, —NH₂, methyl,ethyl, n-propyl, iso-propyl, —OCH₃, —OCH₂CH₃, —OCH₂CH₂CH₃, —OCH(CH₃)₂,—NHCH₃, —NHCH₂CH₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, —N(CH₃)₂, —N(CH₃)(CH₂CH₃),—N(CH₃)(CH₂CH₂CH₃), —N(CH₃)(CH(CH₃)₂), —N(CH₂CH₃)₂,—N(CH₂CH₃)(CH₂CH₂CH₃), —N(CH₂CH₃)(CH(CH₃)₂), —N(CH₂CH₂CH₃)₂,—N(CH₂CH₂CH₃)(CH(CH₃)₂), and —N(CH(CH₃)₂)₂. In a still further aspect,R⁹ is phenyl substituted with 0, 1, 2, or 3 groups independentlyselected from fluorine, chlorine, —CF₃, —NH₂, methyl, ethyl, —OCH₃,—OCH₂CH₃, —OCH(CH₃)₂, —NHCH₃, —NHCH₂CH₃, —N(CH₃)₂, —N(CH₃)(CH₂CH₃), and—N(CH₂CH₃)₂. In yet a further aspect, R⁹ is phenyl substituted with 0,1, 2, or 3 groups independently selected from fluorine, chlorine,methyl, —CF₃, —NH₂, —OCH₃, —NHCH₃, and —N(CH₃)₂.

d. R¹⁰ Groups

In one aspect, R¹⁰ is selected from C1-C4 alkyl and phenyl substitutedwith 0, 1, 2, or 3 groups independently selected from halogen and C1-C4alkyl.

In a further aspect, R¹⁰ is C1-C4 alkyl. In a still further aspect, R¹⁰is selected from methyl, ethyl, n-propyl, and iso-propyl. In yet afurther aspect, R¹⁰ is selected from methyl and ethyl. In an evenfurther aspect, R¹⁰ is ethyl. In a still further aspect, R¹⁰ is methyl.

In a further aspect, R¹⁰ is phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from halogen and C1-C4 alkyl. In a still furtheraspect, R¹⁰ is phenyl substituted with 0, 1, or 2 groups independentlyselected from halogen and C1-C4 alkyl. In yet a further aspect, R¹⁰ isphenyl substituted with 0 or 1 group selected from halogen and C1-C4alkyl. In an even further aspect, R¹⁰ is phenyl monosubstituted with agroup selected from halogen and C1-C4 alkyl. In a still further aspect,R¹⁰ is unsubstituted phenyl.

In a further aspect, R¹⁰ is phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl, n-propyl,iso-propyl, n-butyl, sec-butyl, iso-butyl, and tert-butyl. In a stillfurther aspect, R¹⁰ is phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from fluorine, chlorine, methyl, ethyl, n-propyl,and iso-propyl. In yet a further aspect, R¹⁰ is phenyl substituted with0, 1, 2, or 3 groups independently selected from fluorine, chlorine,methyl, and ethyl. In an even further aspect, R¹⁰ is phenyl substitutedwith 0, 1, 2, or 3 groups independently selected from fluorine,chlorine, and methyl.

In a further aspect, R¹⁰ is phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from methyl, ethyl, n-propyl, iso-propyl,n-butyl, sec-butyl, iso-butyl, and tert-butyl. In a still furtheraspect, R¹⁰ is phenyl substituted with 0, 1, 2, or 3 groupsindependently selected from methyl, ethyl, n-propyl, and iso-propyl. Inyet a further aspect, R¹⁰ is phenyl substituted with 0, 1, 2, or 3groups independently selected from methyl, and ethyl. In an even furtheraspect, R¹⁰ is phenyl substituted with 0, 1, 2, or 3 methyl groups.

2. Example Photocatalyst Structures

In one aspect, an acridinium photocatalyst can be present as:

F. Methods of Making Substituted Arenes

In one aspect, methods of making a compound having a structurerepresented by a formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl; wherein Z is selected from halogen, —CN, —NH₂, —OH, C1-C8alkenyl, C1-C8 alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, arylamino, diarylamino, C1-C8 alkarylamino,—NNR⁴, —OC(═O)R⁵, and Ar¹; wherein R⁴ is selected from hydrogen andC1-C8 alkyl; wherein R⁵ is selected from C1-C8 alkyl; wherein Ar¹ is a3- to 6-membered heterocycle substituted with 0, 1, 2, or 3 groupsindependently selected from halogen and C1-C8 alkyl, the methodcomprising the steps of: (a) reacting a compound having a structurerepresented by a formula:

with a nucleophile selected from water, ammonia, a halide, a cyanide, analcohol, a thiol, an amine, a hydrazine, a carbamate, a carboxylic acid,and an alkene, in the presence of a catalytically effective amount of anacridinium photocatalyst; and (b) reacting with an oxidant, therebyforming the compound are disclosed. In a further aspect, the electrondonating group is selected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8alkoxy, C1-C8 thioalkoxy, C1-C8 silyloxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, —OAr², and Ar²;wherein each of R⁶ and R⁷ is independently selected from C1-C8 alkyl;and wherein Ar² is selected from aryl and heteroaryl and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen and C1-C8alkyl. In a still further aspect, the electron donating group isselected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶,—NHC(═O)R⁷, and Ar²; wherein each of R⁶ and R⁷ is independently selectedfrom C1-C8 alkyl; and wherein Ar² is selected from aryl and heteroaryland substituted with 0, 1, 2, or 3 groups independently selected fromhalogen and C1-C8 alkyl.

In one aspect, methods of making a compound having a structurerepresented by a formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl; or wherein each of Q² and Q⁴ is CR² and wherein eachoccurrence of R² are optionally covalently bonded and, together with theintermediate atoms, comprise a 5- to 6-membered cycle or heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); wherein Zis selected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8 alkoxy,C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; wherein Ar¹ is a 3- to 6-membered heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen and C1-C8 alkyl, the method comprising the steps of: (a)reacting a compound having a structure represented by a formula:

with a nucleophile selected from water, ammonia, a halide, a cyanide, analcohol, a thiol, an amine, a hydrazine, a carbamate, a carboxylic acid,and an alkene, in the presence of a catalytically effective amount of anacridinium photocatalyst; and (b) reacting with an oxidant, therebyforming the compound are disclosed. In a further aspect, the electrondonating group is selected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8alkoxy, C1-C8 thioalkoxy, C1-C8 silyloxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, —OAr², and Ar²;wherein each of R⁶ and R⁷ is independently selected from C1-C8 alkyl;and wherein Ar² is selected from aryl and heteroaryl and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen and C1-C8alkyl. In a still further aspect, the electron donating group isselected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶,—NHC(═O)R⁷, and Ar²; wherein each of R⁶ and R⁷ is independently selectedfrom C1-C8 alkyl; and wherein Ar² is selected from aryl and heteroaryland substituted with 0, 1, 2, or 3 groups independently selected fromhalogen and C1-C8 alkyl.

In one aspect, methods of making a compound having a structurerepresented by a formula selected from:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle substituted with 0, 1, 2, or 3groups independently selected from halogen, C1-C8 alkyl, C1-C8 alkoxy,and —C(═O)NR^(3a)R^(3b); wherein each of R^(3a) and R^(3b) isindependently selected from hydrogen and C1-C4 alkyl; wherein Z isselected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8 alkoxy,C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; and wherein Ar¹ is a 3- to 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen and C1-C8 alkyl, the method comprising the steps of: (a)reacting a compound having a structure represented by a formula selectedfrom:

with a nucleophile selected from water, ammonia, a halide, a cyanide, analcohol, a thiol, an amine, a hydrazine, a carbamate, a carboxylic acid,and an alkene, in the presence of a catalytically effective amount of anacridinium photocatalyst; and (b) reacting with an oxidant, therebyforming the compound are disclosed. In a further aspect, the electrondonating group is selected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8alkoxy, C1-C8 thioalkoxy, C1-C8 silyloxy, C1-C8 alkylamino,(C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶, —NHC(═O)R⁷, —OAr², and Ar²;wherein each of R⁶ and R⁷ is independently selected from C1-C8 alkyl;and wherein Ar² is selected from aryl and heteroaryl and substitutedwith 0, 1, 2, or 3 groups independently selected from halogen and C1-C8alkyl. In a still further aspect, the electron donating group isselected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶,—NHC(═O)R⁷, and Ar²; wherein each of R⁶ and R⁷ is independently selectedfrom C1-C8 alkyl; and wherein Ar² is selected from aryl and heteroaryland substituted with 0, 1, 2, or 3 groups independently selected fromhalogen and C1-C8 alkyl.

In a further aspect, the catalytically effective amount is of from about0.01 mol % to about 15 mol %. In a still further aspect, thecatalytically effective amount is of from about 0.01 mol % to about 12mol %. In yet a further aspect, the catalytically effective amount is offrom about 0.01 mol % to about 10 mol %. In an even further aspect, thecatalytically effective amount is of from about 0.01 mol % to about 7mol %. In a still further aspect, the catalytically effective amount isof from about 0.01 mol % to about 5 mol %. In yet a further aspect, thecatalytically effective amount is of from about 0.01 mol % to about 2mol %. In an even further aspect, the catalytically effective amount isof from about 0.01 mol % to about 1 mol %. In a still further aspect,the catalytically effective amount is of from about 0.01 mol % to about0.1 mol %.

In a further aspect, the catalytically effective amount is of from about0.1 mol % to about 10 mol %. In a still further aspect, thecatalytically effective amount is of from about 0.1 mol % to about 7 mol%. In a still further aspect, the catalytically effective amount is offrom about 0.1 mol % to about 5 mol %. In yet a further aspect, thecatalytically effective amount is of from about 0.1 mol % to about 2 mol%. In an even further aspect, the catalytically effective amount is offrom about 0.1 mol % to about 1 mol %. In a still further aspect, thecatalytically effective amount is 5 mol %.

In a further aspect, the catalytically effective amount is of from about0.1 mol % to about 15 mol %. In a still further aspect, thecatalytically effective amount is of from about 1 mol % to about 15 mol%. In yet a further aspect, the catalytically effective amount is offrom about 2 mol % to about 15 mol %. In an even further aspect, thecatalytically effective amount is of from about 5 mol % to about 15 mol%. In a still further aspect, the catalytically effective amount is offrom about 7 mol % to about 15 mol %. In yet a further aspect, thecatalytically effective amount is of from about 10 mol % to about 15 mol%. In an even further aspect, the catalytically effective amount is offrom about 12 mol % to about 15 mol %.

In a further aspect, the acridinium photocatalyst has a structurerepresented by a formula:

wherein X is selected from BF₄, TfO, PF₆, and ClO₄; wherein each ofR^(8a), R^(8b), R^(8c), R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′)is independently selected from hydrogen, halogen, —CF₃, —NH₂, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 dialkylamino, and phenylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino; wherein R⁹ is selected from C1-C4 alkyl andphenyl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino; and wherein R¹⁰ is selected from C1-C4alkyl and phenyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen and C1-C4 alkyl.

In a further aspect, the acridinium photocatalyst has a structureselected from:

In a further aspect, the acridinium photocatalyst has a structure:

As used herein, the term “nucleophile” refers to a molecule, atom, orion that is capable of forming a chemical bond to its reaction partnerby donating electrons. Exemplary nucleophiles are well known by thoseskilled in the art and include, but are not limited to, water, ammonia,halides, cyanides, alcohols, thiols, amines, hydrazines, carbamates,carboxylic acids, and alkenes.

In a further aspect, the nucleophile is a halide. Exemplary halides arewell known by those skilled in the art and include, but are not limitedto, ammonium fluoride, cesium fluoride, lithium chloride, triethylaminehydrochloride, and triethylamine hydrofluoride.

In a further aspect, the nucleophile is an amine. Exemplary aminesinclude, but are not limited to, ammonium bicarbonate.

As used herein the terms “oxidant” and “oxidizing agent” refer to anyspecies that is capable of accepting or taking electrons from anotherspecies. Exemplary oxidants are well known by those skilled in the artand include, but are not limited to, molecular oxygen,2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO), ozone, andhydrogen peroxide. In a further aspect, the oxidant is molecular oxygen.In a still further aspect, the oxidant is TEMPO. In yet a furtheraspect, the TEMPO is in solution with the acridinium photocatalyst.

In a further aspect, the method further comprises reacting the compoundand the nucleophile in the presence of a catalytically effective amountof an additive. In a still further aspect, the additive is selected fromTEMPO, N-hydroxyphthalimide, galvinoxyl radical,2,2-diphenyl-1-picrylhydrazyl (DPPH), 9-azabicyclo[3.3.1] nonane N-oxylradical (ABNO), and 2,6-di-tert-butyl-4-methylphenol (BHT). In yet afurther aspect, the additive is TEMPO. In an even further aspect, theTEMPO is in solution with the acridinium photocatalyst.

In a further aspect, the catalytically effective amount is of from about0.01 mol % to about 10 mol %. In a still further aspect, thecatalytically effective amount is of from about 0.01 mol % to about 7mol %. In yet a further aspect, the catalytically effective amount is offrom about 0.01 mol % to about 5 mol %. In an even further aspect, thecatalytically effective amount is of from about 0.01 mol % to about 2mol %. In a still further aspect, the catalytically effective amount isof from about 0.01 mol % to about 1 mol %. In yet a further aspect, thecatalytically effective amount is of from about 0.01 mol % to about 0.1mol %.

In a further aspect, the catalytically effective amount is of from about0.1 mol % to about 5 mol %. In a still further aspect, the catalyticallyeffective amount is of from about 0.1 mol % to about 2 mol %. In yet afurther aspect, the catalytically effective amount is of from about 0.1mol % to about 1 mol %. In an even further aspect, the catalyticallyeffective amount is 2 mol %.

In a further aspect, the catalytically effective amount is of from about0.1 mol % to about 10 mol %. In a still further aspect, thecatalytically effective amount is of from about 1 mol % to about 10 mol%. In yet a further aspect, the catalytically effective amount is offrom about 2 mol % to about 10 mol %. In an even further aspect, thecatalytically effective amount is of from about 5 mol % to about 10 mol%. In a still further aspect, the catalytically effective amount is offrom about 7 mol % to about 10 mol %.

In a further aspect, the method further comprises reacting the compoundand the nucleophile in the presence of visible light. In a still furtheraspect, the visible light is from about 365 nm to about 480 nm. In yet afurther aspect, the visible light is from about 365 nm to about 450 nm.In an even further aspect, the visible light is from about 365 nm toabout 420 nm. In a still further aspect, the visible light is from about365 nm to about 400 nm. In yet a further aspect, the visible light isfrom about 365 nm to about 380 nm. In an even further aspect, thevisible light is from about 380 nm to about 480 nm. In a still furtheraspect, the visible light is from about 400 nm to about 480 nm. In yet afurther aspect, the visible light is from about 420 nm to about 480 nm.In an even further aspect, the visible light is from about 450 nm toabout 480 nm.

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the following Reaction Schemes, asdescribed and exemplified below. In certain specific examples, thedisclosed compounds can be prepared by Route I and Route II, asdescribed and exemplified below. The following examples are provided sothat the invention might be more fully understood, are illustrativeonly, and should not be construed as limiting.

1. Route I

In one aspect, para-substituted arenes can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 1.3, and similar compounds, can beprepared according to reaction Scheme 1B above. Thus, compounds of type1.6 can be prepared by an aromatic C—H functionalization reaction of anappropriate arene, e.g., 1.4 as shown above. Appropriate arenes arecommercially available or prepared by methods known to one skilled inthe art. The aromatic C—H functionalization reaction is carried out inthe presence of an appropriate amine, e.g., 1.5 as shown above, which iscommercially available or prepared by methods known to one skilled inthe art, an appropriate catalyst, e.g., 5 mol % Mes-2,7-Me₂Acr-PhBF₄ and20 mol % TEMPO, and an appropriate oxidant, e.g., molecular oxygen, atan appropriate temperature, e.g., 23° C., for an appropriate period oftime, e.g., 24 h. As can be appreciated by one skilled in the art, theabove reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 1.4 and 1.5), can be substitutedin the reaction to provide para-substituted arenes similar to Formula1.6.

Thus, in one aspect, the invention relates to a method of making acompound, the method comprising the step of reacting a compound having astructure represented by a formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl; with a second compound having a structure represented by aformula:

H—Z,

wherein Z is selected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; and wherein Ar¹ is a 3- to 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen and C1-C8 alkyl; in the presence of a catalyticallyeffective amount of an acridinium photocatalyst and an oxidant, therebyforming a para-substituted arene having a structure represented by aformula:

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

2. Route II

In one aspect, ortho-substituted arenes can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 2.2, and similar compounds, can beprepared according to reaction Scheme 2B above. Thus, compounds of type1.7 can be prepared by an aromatic C—H functionalization reaction of anappropriate arene, e.g., 1.4 as shown above. Appropriate arenes arecommercially available or prepared by methods known to one skilled inthe art. The aromatic C—H functionalization reaction is carried out inthe presence of an appropriate amine, e.g., 1.5 as shown above, which iscommercially available or prepared by methods known to one skilled inthe art, an appropriate catalyst, e.g., 5 mol % Mes-2,7-Me₂Acr-PhBF₄ and20 mol % TEMPO, and an appropriate oxidant, e.g., molecular oxygen, atan appropriate temperature, e.g., 23° C., for an appropriate period oftime, e.g., 24 h. As can be appreciated by one skilled in the art, theabove reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 1.4 and 1.5), can be substitutedin the reaction to provide ortho-substituted arenes similar to Formula1.7.

Thus, in one aspect, the invention relates to a method of making acompound, the method comprising the step of reacting a compound having astructure represented by a formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl; or wherein each of Q² and Q⁴ is CR² and wherein eachoccurrence of R² are optionally covalently bonded and, together with theintermediate atoms, comprise a 5- to 6-membered cycle or heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); with asecond compound having a structure represented by a formula:

H—Z,

wherein Z is selected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; and wherein Ar¹ is a 3- to 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen and C1-C8 alkyl; in the presence of a catalyticallyeffective amount of an acridinium photocatalyst and an oxidant, therebyforming an ortho-substituted arene having a structure represented by aformula:

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

3. Route III

In one aspect, substituted arenes can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 3.2, and similar compounds, can beprepared according to reaction Scheme 3B above. Thus, compounds of type3.4 can be prepared by an aromatic C—H functionalization reaction of anappropriate arene, e.g., 3.3 as shown above. Appropriate arenes arecommercially available or prepared by methods known to one skilled inthe art. The aromatic C—H functionalization reaction is carried out inthe presence of an appropriate amine, e.g., 1.5 as shown above, which iscommercially available or prepared by methods known to one skilled inthe art, an appropriate catalyst, e.g., 5 mol % Mes-2,7-Me₂Acr-PhBF₄ and20 mol % TEMPO, and an appropriate oxidant, e.g., molecular oxygen, atan appropriate temperature, e.g., 23° C., for an appropriate period oftime, e.g., 24 h. As can be appreciated by one skilled in the art, theabove reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 3.3 and 1.5), can be substitutedin the reaction to provide ortho-substituted arenes similar to Formula3.2.

Thus, in one aspect, the invention relates to a method of making acompound, the method comprising the step of reacting a compound having astructure represented by a formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein Q³ is selected from N andCR²; wherein each occurrence of R¹ and R² is independently selected fromhydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b);or wherein R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 5- to 6-membered cycle or heterocyclehaving 0, 1, or 2 heteroatoms and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b); wherein each of R^(3a) and R^(3b) is independentlyselected from hydrogen and C1-C4 alkyl; or wherein each of Q² and Q⁴ isCR² and wherein each occurrence of R² are optionally covalently bondedand, together with the intermediate atoms, comprise a 5- to 6-memberedcycle or heterocycle substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b); with a second compound having a structurerepresented by a formula:

H—Z,

wherein Z is selected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; and wherein Ar¹ is a 3- to 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen and C1-C8 alkyl; in the presence of a catalyticallyeffective amount of an acridinium photocatalyst and an oxidant, therebyforming a substituted arene having a structure represented by a formula:

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

4. Route IV

In one aspect, substituted arenes can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 4.2, and similar compounds, can beprepared according to reaction Scheme 4B above. Thus, compounds of type4.4 can be prepared by an aromatic C—H functionalization reaction of anappropriate arene, e.g., 4.3 as shown above. Appropriate arenes arecommercially available or prepared by methods known to one skilled inthe art. The aromatic C—H functionalization reaction is carried out inthe presence of an appropriate amine, e.g., 1.5 as shown above, which iscommercially available or prepared by methods known to one skilled inthe art, an appropriate catalyst, e.g., 5 mol % Mes-2,7-Me₂Acr-PhBF₄ and20 mol % TEMPO, and an appropriate oxidant, e.g., molecular oxygen, atan appropriate temperature, e.g., 23° C., for an appropriate period oftime, e.g., 24 h. As can be appreciated by one skilled in the art, theabove reaction provides an example of a generalized approach whereincompounds similar in structure to the specific reactants above(compounds similar to compounds of type 4.3 and 1.5), can be substitutedin the reaction to provide ortho-substituted arenes similar to Formula4.2.

Thus, in one aspect, the invention relates to a method of making acompound, the method comprising the step of reacting a compound having astructure represented by a formula:

wherein E is an electron donating group; wherein Q¹ is selected from Nand CR¹; wherein each of Q² and Q⁴ is independently selected from N andCR²; wherein each occurrence of R¹ and R² is independently selected fromhydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b);or wherein R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 5- to 6-membered cycle or heterocyclehaving 0, 1, or 2 heteroatoms and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b); wherein each of R^(3a) and R^(3b) is independentlyselected from hydrogen and C1-C4 alkyl; or wherein each of Q² and Q⁴ isCR² and wherein each occurrence of R² are optionally covalently bondedand, together with the intermediate atoms, comprise a 5- to 6-memberedcycle or heterocycle substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b); with a second compound having a structurerepresented by a formula:

H—Z,

wherein Z is selected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8alkoxy, C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; and wherein Ar¹ is a 3- to 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen and C1-C8 alkyl; in the presence of a catalyticallyeffective amount of an acridinium photocatalyst and an oxidant, therebyforming a substituted arene having a structure represented by a formula:

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

G. Methods of Aminating Arenes

In one aspect, methods of aminating an activated arene in the presenceof an acridinium photocatalyst are disclosed.

In one aspect, methods of aminating an activated arene in the absence ofa transition metal catalyst are disclosed. Exemplary transition metalcatalysts are well known to those of skill in the art and include, butare not limited to, palladium-, platinum-, cobalt-, manganese-, andnickel-based catalysts.

In a further aspect, the activated arene has a structure represented bya formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); and whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl.

In a further aspect, the activated arene has a structure represented bya formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); and whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl.

In a further aspect, the activated arene has a structure represented bya formula selected from:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle substituted with 0, 1, 2, or 3groups independently selected from halogen, C1-C8 alkyl, C1-C8 alkoxy,and —C(═O)NR^(3a)R^(3b); wherein each of R^(3a) and R^(3b) isindependently selected from hydrogen and C1-C4 alkyl; wherein Z isselected from halogen, —CN, —NH₂, —OH, C1-C8 alkenyl, C1-C8 alkoxy,C1-C8 thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino,arylamino, diarylamino, C1-C8 alkarylamino, —NNR⁴, —OC(═O)R⁵, and Ar¹;wherein R⁴ is selected from hydrogen and C1-C8 alkyl; wherein R⁵ isselected from C1-C8 alkyl; and wherein Ar¹ is a 3- to 6-memberedheterocycle substituted with 0, 1, 2, or 3 groups independently selectedfrom halogen and C1-C8 alkyl.

In a further aspect, the acridinium photocatalyst has a structurerepresented by a formula:

wherein X is selected from BF₄, TfO, PF₆, and ClO₄; wherein each ofR^(8a), R^(8b), R^(8c), R^(8d), R_(8a′), R^(8b′), R^(8c′), and R^(8d′)is independently selected from hydrogen, halogen, —CF₃, —NH₂, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 dialkylamino, and phenylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino; wherein R⁹ is selected from C1-C4 alkyl andphenyl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino; and wherein R¹⁰ is selected from C1-C4alkyl and phenyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen and C1-C4 alkyl.

In a further aspect, the acridinium photocatalyst has a structureselected from:

In a further aspect, the acridinium photocatalyst has a structure:

The compounds of this invention can be prepared by employing reactionsas shown in the following schemes, in addition to other standardmanipulations that are known in the literature, exemplified in theexperimental sections or clear to one skilled in the art. For clarity,examples having a single substituent are shown where multiplesubstituents are allowed under the definitions disclosed herein.

Reactions used to generate the compounds of this invention are preparedby employing reactions as shown in the following Reaction Schemes, asdescribed and exemplified below. In certain specific examples, thedisclosed compounds can be prepared by Route I and Route II, asdescribed and exemplified below. The following examples are provided sothat the invention might be more fully understood, are illustrativeonly, and should not be construed as limiting.

1. Route I

In one aspect, para-substituted anilines can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 5.1, and similar compounds, can beprepared according to reaction Scheme 5B above. Thus, compounds of type5.3 can be prepared by an aromatic C—H functionalization reaction of anappropriate arene, e.g., 1.4 as shown above. Appropriate arenes arecommercially available or prepared by methods known to one skilled inthe art. The aromatic C—H functionalization reaction is carried out inthe presence of an appropriate source of ammonia, e.g., ammonium salt5.2 as shown above, which is commercially available or prepared bymethods known to one skilled in the art, an appropriate catalyst, e.g.,5 mol % Mes-2,7-Me₂Acr-PhBF₄ and 20 mol % TEMPO, and an appropriateoxidant, e.g., molecular oxygen, at an appropriate temperature, e.g.,23° C., for an appropriate period of time, e.g., 24 h. As can beappreciated by one skilled in the art, the above reaction provides anexample of a generalized approach wherein compounds similar in structureto the specific reactants above (compounds similar to compounds of type1.4 and 5.2), can be substituted in the reaction to providepara-substituted anilines similar to Formula 5.3.

Thus, in one aspect, the invention relates to a method of making acompound, the method comprising the step of reacting a compound having astructure represented by a formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl; with a second compound having a structure represented by aformula:

H—Z,

wherein Z is —NH₂; in the presence of a catalytically effective amountof an acridinium photocatalyst and an oxidant, thereby forming apara-substituted aniline having a structure represented by a formula:

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

2. Route II

In one aspect, ortho-substituted anilines can be prepared as shownbelow.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 6.1, and similar compounds, can beprepared according to reaction Scheme 6B above. Thus, compounds of type5.4 can be prepared by an aromatic C—H functionalization reaction of anappropriate arene, e.g., 1.4 as shown above. Appropriate arenes arecommercially available or prepared by methods known to one skilled inthe art. The aromatic C—H functionalization reaction is carried out inthe presence of an appropriate source of ammonia, e.g., ammonium salt5.2 as shown above, which is commercially available or prepared bymethods known to one skilled in the art, an appropriate catalyst, e.g.,5 mol % Mes-2,7-Me₂Acr-PhBF₄ and 20 mol % TEMPO, and an appropriateoxidant, e.g., molecular oxygen, at an appropriate temperature, e.g.,23° C., for an appropriate period of time, e.g., 24 h. As can beappreciated by one skilled in the art, the above reaction provides anexample of a generalized approach wherein compounds similar in structureto the specific reactants above (compounds similar to compounds of type1.4 and 5.2), can be substituted in the reaction to provideortho-substituted anilines similar to Formula 5.4.

Thus, in one aspect, the invention relates to a method of making acompound, the method comprising the step of reacting a compound having astructure represented by a formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(═O)NR^(3a)R^(3b); wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); whereineach of R^(3a) and R^(3b) is independently selected from hydrogen andC1-C4 alkyl; or wherein each of Q² and Q⁴ is CR² and wherein eachoccurrence of R² are optionally covalently bonded and, together with theintermediate atoms, comprise a 5- to 6-membered cycle or heterocyclesubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b); with asecond compound having a structure represented by a formula:

H—Z,

wherein Z is —NH₂; in the presence of a catalytically effective amountof an acridinium photocatalyst and an oxidant, thereby forming anortho-substituted aniline having a structure represented by a formula:

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

3. Route III

In one aspect, substituted arenes can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 7.1, and similar compounds, can beprepared according to reaction Scheme 7B above. Thus, compounds of type7.2 can be prepared by an aromatic C—H functionalization reaction of anappropriate arene, e.g., 3.3 as shown above. Appropriate arenes arecommercially available or prepared by methods known to one skilled inthe art. The aromatic C—H functionalization reaction is carried out inthe presence of an appropriate source of ammonia, e.g., ammonium salt5.2 as shown above, which is commercially available or prepared bymethods known to one skilled in the art, an appropriate catalyst, e.g.,5 mol % Mes-2,7-Me₂Acr-PhBF₄ and 20 mol % TEMPO, and an appropriateoxidant, e.g., molecular oxygen, at an appropriate temperature, e.g.,23° C., for an appropriate period of time, e.g., 24 h. As can beappreciated by one skilled in the art, the above reaction provides anexample of a generalized approach wherein compounds similar in structureto the specific reactants above (compounds similar to compounds of type3.3 and 5.2), can be substituted in the reaction to provide substitutedarenes similar to Formula 7.1.

Thus, in one aspect, the invention relates to a method of making acompound, the method comprising the step of reacting a compound having astructure represented by a formula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein Q² is selected from N andCR²; wherein each occurrence of R¹ and R² is independently selected fromhydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b);wherein R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 5- to 6-membered cycle or heterocyclehaving 0, 1, or 2 heteroatoms and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b); wherein each of R^(3a) and R^(3b) is independentlyselected from hydrogen and C1-C4 alkyl; or wherein each of Q² and Q⁴ isCR² and wherein each occurrence of R² are optionally covalently bondedand, together with the intermediate atoms, comprise a 5- to 6-memberedcycle or heterocycle substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b); with a second compound having a structurerepresented by a formula:

H—Z,

wherein Z is —NH₂; in the presence of a catalytically effective amountof an acridinium photocatalyst and an oxidant, thereby forming asubstituted arene having a structure represented by a formula:

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

4. Route IV

In one aspect, substituted arenes can be prepared as shown below.

Compounds are represented in generic form, with substituents as noted incompound descriptions elsewhere herein. A more specific example is setforth below.

In one aspect, compounds of type 8.1, and similar compounds, can beprepared according to reaction Scheme 8B above. Thus, compounds of type8.2 can be prepared by an aromatic C—H functionalization reaction of anappropriate arene, e.g., 4.3 as shown above. Appropriate arenes arecommercially available or prepared by methods known to one skilled inthe art. The aromatic C—H functionalization reaction is carried out inthe presence of an appropriate source of ammonia, e.g., ammonium salt5.2 as shown above, which is commercially available or prepared bymethods known to one skilled in the art, an appropriate catalyst, e.g.,5 mol % Mes-2,7-Me₂Acr-PhBF₄ and 20 mol % TEMPO, and an appropriateoxidant, e.g., molecular oxygen, at an appropriate temperature, e.g.,23° C., for an appropriate period of time, e.g., 24 h. As can beappreciated by one skilled in the art, the above reaction provides anexample of a generalized approach wherein compounds similar in structureto the specific reactants above (compounds similar to compounds of type4.3 and 5.2), can be substituted in the reaction to provide substitutedarenes similar to Formula 8.1.

Thus, in one aspect, the invention relates to a method of making acompound, the method comprising the step of reacting a compound having astructure represented by a formula:

wherein E is an electron donating group; wherein Q¹ is selected from Nand CR¹; wherein each of Q² and Q⁴ is independently selected from N andCR²; wherein each occurrence of R¹ and R² is independently selected fromhydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b);wherein R¹ and R² are optionally covalently bonded and, together withthe intermediate atoms, comprise a 5- to 6-membered cycle or heterocyclehaving 0, 1, or 2 heteroatoms and substituted with 0, 1, 2, or 3 groupsindependently selected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b); wherein each of R^(3a) and R^(3b) is independentlyselected from hydrogen and C1-C4 alkyl; or wherein each of Q² and Q⁴ isCR² and wherein each occurrence of R² are optionally covalently bondedand, together with the intermediate atoms, comprise a 5- to 6-memberedcycle or heterocycle substituted with 0, 1, 2, or 3 groups independentlyselected from halogen, C1-C8 alkyl, C1-C8 alkoxy, and—C(═O)NR^(3a)R^(3b); with a second compound having a structurerepresented by a formula:

H—Z,

wherein Z is —NH₂; in the presence of a catalytically effective amountof an acridinium photocatalyst and an oxidant, thereby forming asubstituted arene having a structure represented by a formula:

It is contemplated that each disclosed method can further compriseadditional steps, manipulations, and/or components. It is alsocontemplated that any one or more step, manipulation, and/or componentcan be optionally omitted from the invention. It is understood that adisclosed method can be used to provide the disclosed compounds. It isalso understood that the products of the disclosed methods can beemployed in the disclosed methods of using.

H. Examples

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how thecompounds, compositions, articles, devices and/or methods claimed hereinare made and evaluated, and are intended to be purely exemplary of theinvention and are not intended to limit the scope of what the inventorsregard as their invention. Efforts have been made to ensure accuracywith respect to numbers (e.g., amounts, temperature, etc.), but someerrors and deviations should be accounted for. Unless indicatedotherwise, parts are parts by weight, temperature is in ° C. or is atambient temperature, and pressure is at or near atmospheric.

The Examples are provided herein to illustrate the invention, and shouldnot be construed as limiting the invention in any way. Examples areprovided herein to illustrate the invention and should not be construedas limiting the invention in any way.

1. Synthesis of 1-(4-Methoxyphenyl)-1H-pyrazole

To a flame-dried 2 dram vial containing a Teflon-coated magnetic stirbar was added 12 mg of 9-mesityl-2,7-dimethyl-10-phenylacridiniumtetrafluoroborate (25 μml, 0.05 equiv.), 68 mg of pyrazole (1.0 mmol, 2equiv.), and 16 mg of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (0.1 mmol,0.1 equiv.). Anhydrous 1,2-dichloroethane (DCE) was added (5.0 mL),followed by 54 μL of anisole (0.5 mmol, 1 equiv.). The vial was sealedwith a Teflon-lined septum screw cap. The septum was pierced with adisposable steel needle connected to an oxygen-filled balloon. A ventneedle was inserted and the reaction medium was sparged for 5 minutes bybubbling oxygen through the mixture. The vent needle was removed, andthe oxygen balloon was maintained, providing approximately 1 atm ofoxygen to the vial headspace for the course of the reaction. The vialwas positioned on a stir plate approximately 10 cm from a Par38 LED lampsupplying blue light (λ=440-460 nm). After irradiation for 20 hours, thereaction mixture was passed through a short pad of silica gel, which wasrinsed with an equal volume of dichloromethane. The crude product wasconcentrated in vacuo and purified by column chromatography on silicagel with hexanes/ethyl acetate (20:1 v/v) as the eluent. A colorless oilwas obtained as a 8:1 mixture of 1-(4-methoxyphenyl)-1H-pyrazole and1-(2-methoxyphenyl)-1H-pyrazole, yielding 69 mg of material (79% yield).

2. Substitution of Electron-Rich Arenes

It was envisioned that addition of various nucleophiles to electron-richarenes could be achieved. The initial reactions were performed inaerobic conditions to determine whether molecular oxygen could act as aterminal oxidant. Molecular oxygen was chosen due to its wide abundanceand the minimal waste produced in comparison to other heavily utilizedoxidants, such as diacetoxyiodobenzene or metal co-catalysts.

The initial results are illustrated in Table 1. Anisole was utilized asthe oxidizable arene and 1,2,4-triazole as the nucleophile. As shownbelow, the para-functionalized product was observed in a greaterproportion than the ortho isomer. Using a significant excess of eitherthe amine or the arene did not increase the yield appreciably (Entries 3and 4). Yields using 1,2,4-triazole as the nucleophile appeared tostagnate around 40%. Without wishing to be bound by theory, it ishypothesized that this may be due to the lack of amine solubility.Manipulation of either the solvent, the base, the time, or the additionof a thiol did not appear to facilitate an increase in yield for thetriazole amination reactions. Furthermore, when the vial was spargedwith nitrogen or argon in place of oxygen, only trace amounts of productwere observed (Entry 7).

TABLE 1

Yield^(a) Entry Conditions (%) p:o 1 Standard conditions as shown 31 6:1above. 2 15 mol % of Ph₂S₂ 28 6:1 3 2 eq. amine 22 6:1 4 2 eq. arene 145:1 5 No balloon, O₂ sparge 17.9 only para 6 O₂ balloon, no O₂ sparge28.1 >100:1 7 Sparge with argon 0.3 only para ^(a)GCMS yield vs.1,3-dimethoxybenzene standard

Next, pyrazole was used as the nucleophile and other oxidants, such asbenzoquinone, hypervalent iodine reagents, and potassium persulfate,were tested (Table 2). The solvent concentration was also varied(Entries 7-9).

TABLE 2

Yield Entry Conditions (%) p:o 1 Standard conditions as shown 40^(a)8.8:1 above. 2 No O₂ <1 — 3 PhI(OAc)₂, no photooxidant <1 — 4 Potassiumpersulfate 9 2:1 5 PhI(OAc)₂ 20^(b) 5:1 6 Benzoquinone, no O₂ 8 7:1 7[0.35M] in DCE 36 6.8:1 8 [0.1M] in DCE 41 5:1 9 [0.05M] in DCE 17 1.3:110 2.5 mmol scale 30^(c) 5:1 ^(a) GCMS yield vs. 1,3-dimethoxybenzenestandard; ^(b)Isolated yield; ^(c)NMR yield vs. hexamethyl disiloxane(HMDS) standard.

3. Evaluation of Substrate Scope

Various aryl ether derivatives were examined and the results illustratedin Table 3. Each reaction was performed using 5 mol %Mes-2,7-Me₂Acr-PhBF₄, 450 nm LEDs, O₂ sparge, and DCE at 23° C. Manysubstituted arenes were tolerant of the reaction conditions; however,for xylene and mesitylene, oxidation to the corresponding aldehyde wasobserved. It is also noteworthy that halogenated substrates weretolerated, as these substrates would be positioned for furtherfunctionalization.

TABLE 3 Compound No. Structure Yield (%) 9

40 (7:1 p:o) 10

31 (7:1 p:o) 11

48 11a

48 12

32 13

16 14

26

4. Evaluation of Photocatalysts

It was observed that the catalyst was not always stable to the aerobicconditions, as indicated by trace amounts of aldehyde detected by ¹H NMRfrom the oxidation of the mesityl substituent on the acridinium. Indeed,the oxidation of Mes-Acr-MeBF₄ under aerobic conditions has beenpreviously reported (Verhoven et al. (2005) J. Am. Chem. Soc. 127,16054). For this reason, several catalyst derivatives were explored(Table 4).

TABLE 4 Catalyst Structure Mes-Acr-MeBF₄

Mes-2,7-Me₂Acr-PhBF₄

Mes-3,6-tBu₂Acr- PhBF₄

Xylyl-Acr-PhBF₄

5. Screening of Additives

After isolating product 15 and resubmitting to reaction conditions, itwas determined that the 1,2,4-triazole adduct could not be recovered. Itwas also determined that 15 had a lower oxidation potential compared toanisole (E_(1/2) ^(ox)=1.87), indicating that it is more prone tooxidation (Scheme 9). When pyrazole adduct 9 was submitted to thephotoredox conditions, only 15% of the product was recovered (Scheme10).

In order to overcome these complications, a number of additives werescreened (Table 5). A significant increase in the yield was observedwhen catalytic amounts of 2,2,6,6-tetramethyl-1-piperidinyloxy radical(TEMPO) were added to the reaction mixture. Other oxygen-centeredradicals such as 9-azabicyclo[3.3.1] nonane N-oxyl radical (ABNO), or2,6-di-tert-butyl-4-methylphenol (BHT) improved the reactivity ofpyrazole with various arenes (Entries 6 and 7). A full equivalent oftemponium was also attempted in the oxidizing conditions; however, thisled to significant decrease in yield (Entry 5).

After further optimization using TEMPO as an additive, it was determinedthat more dilute conditions (e.g., 1.0M) resulted in a larger yield(Entry 9). Furthermore, use of a newly synthesized acridiniumphotocatalyst, Mes-3,6-tBu₂Acr-PhBF₄, in which the 3 and 6 positions onthe acridinium were functionalized with tert-butyl groups, also improvedyields. Without wishing to be bound by theory, this may be due to thetert-butyl groups blocking the catalyst from nucleophilic addition(Entry 11).

TABLE 5

Yield^(a) Entry Conditions (%) p:o 1 Standard conditions as shown79^(c,d) 8:1 above. 2 Standard conditions as shown 40 8.8:1 abovewithout TEMPO. 3^(b) TEMPO (0.5 equiv.) 33.5 7.6:1 4^(b) TEMPO (1.0equiv.) 28.3 7.9:1 5^(b) Temponium (1.0 equiv.) 16 8.6:1 6 ABNO insteadof TEMPO 60 7.8:1 7 BHT instead of TEMPO 42.2 6.4:1 8 0.5M DCE 45.57.5:1 9 0.1M DCE 57.6 8.1:1 10^(b) 2.5 mol % Mes-2,7-Me₂Acr- 48 8:1PhBF₄ 11 5 mol % Mes-3,6-tBu₂Acr- 62.5 8.1:1 PhBF₄ 12 Pyrazole (1.5equiv.) 53.1 8.5:1 13 Pyrazole (1.0 equiv.) 52.9 8.1:1 14^(b) 2.0 equiv.anisole, 1.0 equiv. 46.1 8:1 pyrazole 15 Air sparge instead of O₂ 35.09.3:1 16^(b) N₂ instead of O₂ 47 8:1 ^(a)GCMS yield vs.1,3-dimethoxybenzene standard; ^(b)0.5M DCE; ^(c)Isolated; ^(d)5 mol %Mes-3,6-tBu₂Acr-PhBF₄.

6. Evaluation of Substrate Scope Using TEMPO

The TEMPO additive was evaluated using a range of substrates and theresults illustrated in Table 6. Each reaction was performed using 5 mol% Mes-2,7-Me₂Acr-PhBF₄, 450 nm LEDs, O₂ sparge, and DCE at 23° C. Withsome arenes, such as 1,3-dimethoxybenzene, the addition of TEMPO had anegative effect on yield. The amination was observed with some 1,2- and1,3-disubstituted benzenes. Additionally, mesitylene and xylenes couldbe aminated without the observance of oxidation side products (compounds21 and 22). This is a significant departure in reactivity compared toprior research. Indeed, previous attempts using a photoredox systemwithout the oxygen-centered radical oxidized the methyl group to thecorresponding aldehyde. This reactivity resembles the oxidation oftoluene derivatives to the corresponding benzoic acids and aldehydes byFukuzumi (Ohkubu et al. (2013) Chem. Intermed. 39, 205). With theaddition of TEMPO, simple alkyl-substituted arene substrates wereeffectively aminated. Halogenated substrates such as 2-chloroanisolewere also tolerant of the reaction conditions. Several aminenucleophiles have been shown to produce the desired amination productsin generally good yields.

TABLE 6 Compound No. Structure Yield (%) p:o 16

21 7:1 17

65 14:1 18

51 5.5:1 19

41 — 20

34 — 21

45 — 22

30 — 23

16 — 24

46 3.3:1 25

60 4:1 26

59 (3.5:1 N1:N2) 6:1 27

Single regioisomer 28

81 (1:1 N1:N4) 6:1 29

6:1 30

45 (2.5:1 N9:N7 — 31

— 32

40 Single regioisomer 33

30 (1:1 N1:N3 34

45 Single regioisomer

While it has been demonstrated that ether derived arenes as well asalkyl-substituted arenes tolerate these conditions, no anilines have yetto produce amination products. Without wishing to be bound by theory,this may be due to the low oxidation potentials of many commerciallyavailable anilines, the rapid back electron transfer, or the slownucleophilic addition.

7. Proposed Mechanism of Photocatalytic Aerobic Aryl Amination

Without wishing to be bound by theory, it is hypothesized that, afterexcitation by light, organic photocatalyst Mes-2,7-Me₂Acr-PhBF₄ canundergo SET from arene A, generating radical cation B (Scheme 11).Subsequent nucleophilic addition of the amine followed by oxidationaffords the desired aminated arene C.

Without wishing to be bound by theory, it is hypothesized that TEMPO mayserve as a hydrogen atom abstraction catalyst. A proposed mechanism ofphotocatalytic aerobic aryl amination using TEMPO is illustrated inScheme 12 below.

8. Counterion Effects

A variety of counterions were evaluated as shown in Scheme 5 below.Without wishing to be bound by theory, the results indicate that the pKaof the conjugate acid may be directly correlated with the reaction yield(FIG. 1).

9. Direct Synthesis of Anilines—Evaluation of Substrate Scope

A variety of substrates were chosen to evaluate the scope of thistechnique towards the direct syntheses of anilines. Each reaction wasperformed using 4.0 equivalents of ammonium carbamate, 5 mol %Mes-2,7-Me₂Acr-PhBF₄, 20 mol % TEMPO, 450 nm LEDs, O₂ sparge, and DCE at23° C. The resulting anilines and their respective yields areillustrated in Table 7.

TABLE 7 Compound No. Structure Yield (%) p:o 35

55 1.5:1 36

68 6:1 37

51 >10:1 38

55 — 39*

40 — 40

60 — *7% of C4 and C6 isomers observed.

10. Cyanation

Biphenyl (77.11 mg, 0.5 mmol), di-tert-butyl-acridinium photocatalyst(14.34 mg, 0.025 mmol) and 0.5 ml of a 4 M, pH 9 phosphate buffer weredissolved in 5 ml of ACN. The reaction mixture was sealed and spargedfor several minutes with 02. After sparging, TMSCN (94.07 μl, 0.75 mmol)was added and the biphasic mixture was stirred vigorously underblue-light irradiation for 18 hours. The reaction mixture was thenconcentrated by rotary evaporation and purified by column chromatography(1:19 EtOAc/Hex) to give and inseparable mixture of the ortho- andpara-functionalized products (71.9 mg, 0.40 mmol, 80.25%). The ratio ofisomers was roughly 5:1 in favor of the para-finctionalized product.

Preliminary results show a promising method for the formation ofbenzonitriles taking advantage of a photoredox-mediated, C—Hfunctionalization pathway. Without wishing to be bound by theory, it isbelieved that the reaction proceeds through the mechanism outlined inScheme 13, below. The photocatalyst, Mes-Acr+ is promoted to excitedstate by blue-light irradiation where is can act as a single electronoxidant, oxidizing the arene, 1 to its corresponding radical cation (2).TMSCN is then employed as the nucleophilic source of cyanide to trap theradical cation. From here, the resulting radical (3) can be trapped with02 giving the aryl-peroxyl radical (4). Intramolecular H-atomabstraction from the peroxyl radical generates a hydroperoxyl radicaland restores aromaticity to give the final benzonitriles product (5).The catalytic cycle is closed by the single electron reduction of O₂ byMes-Acr forming a superoxide radical and regenerating the activephotocatalyst.

The pH 9 buffer is used for this system to inhibit the generation ofHCN, which can retard or prohibit the reaction. Without wishing to bebound by theory, it is believed that additional cooxidants are notnecessary to turn over the catalyst. Polar, non-halogenated solvents arepreferred. Vigorous stirring enhances yield. The presence of waterand/or inorganic base is preferred for the reaction. Without wishing tobe bound by theory, it is believed that phase transfer catalysts are notnecessary to help introduce —CN. Without wishing to be bound by theory,it is believed that changes in concentration have little effect on thereaction (e.g., yield). Both KCN and NaCN can be used, but studiesindicate that TMSCN gives better results (e.g., yield). Exemplaryalternative substrates for this reaction include:

As illustrated in Scheme 14, above, fluorination can be accomplished. Ina glovebox, cesium fluoride (10.0 eq.) was weighed and added to a driedglass vial (2 dram) equipped with a stir bar. This vial was removed fromthe glovebox and the substrate (1.0 eq.), TBAHSO₄ (0.5 eq.), and TEMPO(0.5 eq.) were weighed and added to the vial sequentially. The vial wasthen sealed with a Teflon-lined septum screw cap. The solvent mixture(10:1 DCE:H₂O) was then added. The septum was then pierced with adisposable steel needle connected to an oxygen-filled balloon. A ventneedle was inserted and the reaction medium was sparged for 15 minutesby bubbling oxygen through the mixture. The vent needle was removed, andthe oxygen balloon was maintained, providing approximately 1 atm ofoxygen to the vial headspace for the course of the reaction. Thereaction flask was then placed on a stir plate and illuminated with blueLED lamps (455 nm) for 24 h. After the reaction was completed, thereaction mixture was eluted through a silica plug and the eluent wasanalyzed by GC-MS, using 3-bromotoluene as the internal standard.

CsF was used as the nucleophile, and TBAHSO₄ was used as a phasetransfer reagent to increase fluoride solubility in dichloroethane.Without wishing to be bound by theory, it is believed that the keyactivation step is the single electron oxidation of the arene by anacridinium photocatalyst (Mes-Acr+), as shown in Scheme 15, below.Illumination of the photocatalyst with blue light activates it to itsexcited state (Mes-Acr+*), where it becomes a potent oxidant. Thisspecies then oxidizes the substrate, rendering it susceptible tofluoride attack. (1 to 2). The resulting species can then be convertedto the desired product by H-atom transfer to TEMPO, forming TEMPO-H.TEMPO-H can then be converted back to TEMPO by superoxide, which isgenerated from photocatalyst turnover via oxidation of Mes-Acr· toMes-Acr+.

12. Oxygen Nucleophiles

As shown in Scheme 16, above, oxygen nucleophiles can be used for directC—H functionalization. Piperidinium benzoate (5.0 eq.), catalyst (5 mol%), and TEMPO (0.2 eq.) were weighed out and transferred to aflame-dried 20-mL scintillation vial that was equipped with a stir bar.The dichloroethane (9.00 mL) and deionized water (0.90 mL) weretransferred to the vial via syringe, and the anisole (1.0 eq.) wastransferred via microsyringe. The vial was capped with a rubber septumand sealed with Teflon tape. Oxygen was bubbled through the system forfive minutes to sparge the yellow reaction mixture. The biphasicreaction was stirred vigorously for eighteen hours while beingirradiated by 455 nm blue LED light and cooled by a fan. The reactionmixture was filtered through a silica plug, and the reaction vessel andsilica were washed with dichloromethane and ethyl acetate. The crudeproduct was characterized via GC-MS and ¹H NMR spectroscopy.Purification through column chromatography was performed using a 10%ethyl acetate in hexanes solvent system to yield 11.7 mg (0.05126 mmol)of the desired products (3:1 para:ortho selectivity) in a combined 51.3%isolated yield.

Screening revealed that benzoate salts had the ability to add to arenes.Success was seen when a piperidinium benzoate salt was used as thenucleophile and when the reaction was run at a more dilute concentration(e.g., 0.01M). Modest selectivity can be seen for the formation of thepara product over the ortho product. Selectivity varies with substrate,as arenes with more hindered ortho positions display higher preferencesfor the para product. Without wishing to be bound by theory, Scheme 17below shows the mechanism for the system. Oxidation of the arene (1) bythe excited state acridinium catalyst (Mes-Acr+*) generates the radicalcation intermediate (2) that undergoes nucleophilic attack by thebenzoate anion. Generation of the product (4) occurs through thetransfer of a hydrogen atom to TEMPO to form the TEMPO-H species. TEMPOis regenerated via a superoxide species that results from the oxidationof the radical acridinium (Mes-Acr·) species back to the ground statephotocatalyst (Mes-Acr+).

It will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention. Otherembodiments of the invention will be apparent to those skilled in theart from consideration of the specification and practice of theinvention disclosed herein. It is intended that the specification andexamples be considered as exemplary only, with a true scope and spiritof the invention being indicated by the following claims.

1. A method of making a compound having a structure represented by aformula:

wherein E is an electron donating group; wherein each of Q¹ and Q³ isindependently selected from N and CR¹; wherein each of Q² and Q⁴ isindependently selected from N and CR²; wherein each occurrence of R¹ andR² is independently selected from hydrogen, halogen, C1-C8 alkyl, C1-C8alkoxy, and —C(O)NR^(3a)R^(3b); or wherein R¹ and R² are optionallycovalently bonded and, together with the intermediate atoms, comprise a5- to 6-membered cycle or heterocycle having 0, 1, or 2 heteroatoms andsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(O)NR^(3a)R^(3b); wherein eachof R^(3a) and R^(3b) is independently selected from hydrogen and C1-C4alkyl; wherein Z is selected from ¹⁸F and 13 CN, the method comprisingthe steps of: (a) reacting a compound having a structure represented bya formula:

with a nucleophile selected from a fluoride and a cyanide, in thepresence of a catalytically effective amount of an acridiniumphotocatalyst; and (b) reacting with an oxidant, thereby forming thecompound.
 2. The method of claim 1, wherein the electron donating groupis selected from —OH, —SH, —NH₂, C1-C8 alkyl, C1-C8 alkoxy, C1-C8thioalkoxy, C1-C8 alkylamino, (C1-C8)(C1-C8) dialkylamino, —OC(═O)R⁶,—NHC(═O)R⁷, and Ar²; wherein each of R⁶ and R⁷ is independently selectedfrom C1-C8 alkyl; and wherein Ar² is selected from aryl and heteroaryland substituted with 0, 1, 2, or 3 groups independently selected fromhalogen and C1-C8 alkyl.
 3. The method of claim 1, wherein Z is ¹⁸F.4-8. (canceled)
 9. The method of claim 1, wherein the acridiniumphotocatalyst has a structure represented by a formula:

wherein X is selected from BF₄, TfO, PF₆, and ClO₄; wherein each ofR^(8a), R^(8b), R^(8c), R^(8d), R^(8a′), R^(8b′), R^(8c′), and R^(8d′)is independently selected from hydrogen, halogen, —CF₃, —NH₂, C1-C4alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 dialkylamino, and phenylsubstituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino; wherein R⁹ is selected from C1-C4 alkyl andphenyl substituted with 0, 1, 2, or 3 groups independently selected fromhalogen, —CF₃, —NH₂, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino,(C1-C4)(C1-C4) dialkylamino; and wherein R¹⁰ is selected from C1-C4alkyl and phenyl substituted with 0, 1, 2, or 3 groups independentlyselected from halogen and C1-C4 alkyl.
 10. The method of claim 0,wherein the acridinium photocatalyst has a structure selected from:


11. The method of claim 0, wherein the acridinium photocatalyst has astructure:


12. (canceled)
 13. The method of claim 1, wherein the fluoride isselected from ammonium fluoride, cesium fluoride, and triethylaminehydrofluoride. 14-15. (canceled)
 16. The method of claim 1, wherein theoxidant is molecular oxygen.
 17. The method of claim 1, wherein theoxidant is 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO). 18-20.(canceled)
 21. The method of claim 1, wherein Z is —CN.
 22. The methodof claim 1, wherein the acridinium photocatalyst has a structureselected from:

and wherein the oxidant is 2,2,6,6-tetramethyl-1-piperidinyloxy radical(TEMPO).
 23. The method of claim 1, wherein the compound has a structurerepresented by a formula:


24. The method of claim 1, wherein the compound has a structurerepresented by a formula:


25. The method of claim 1, wherein the compound has a structurerepresented by a formula:

wherein each of Q⁵, Q⁶, Q⁷, and Q⁸ is independently selected from N andCR¹⁴; and wherein each occurrence of R¹⁴ is independently selected fromhydrogen, halogen, C1-C8 alkyl, C1-C8 alkoxy, and —C(═O)NR^(3a)R^(3b).26. The method of claim 1, wherein the compound has a structurerepresented by a formula:

wherein A is selected from CR^(12a)R^(12b), O, S, and NR¹³; wherein eachof R^(12a), R^(12b), and R¹³, when present, is independently selectedfrom hydrogen and C1-C4 alkyl; and wherein each of R^(11a) and R^(11b)is independently selected from hydrogen and C1-C4 alkyl.
 27. The methodof claim 1, wherein the compound has a structure represented by aformula:


28. The method of claim 1, wherein the compound has a structurerepresented by a formula:


29. The method of claim 1, wherein the compound is isotopically-labeled.30. The method of claim 25, wherein the compound contains a radioactiveisotope.
 31. The method of claim 1, wherein the compound is notisotopically-labeled.